#029 - What If Regulatory T Cells Hold the Key to Preterm Birth?

Hello friends 👋

What happens when a mom's immune system loses its tolerance for pregnancy, and a physician-scientist builds an entire lab, and career, around figuring out why? On this episode of At the Bench, hosts Ben Fensterheim and David McCulley sit down with Dr. Jackie Lajiness, a neonatologist and physician-scientist at Indiana University. Dr. Lajiness traces her path from an undergraduate laser spectroscopy lab to an MD-PhD, and shares her current research using a mouse model of regulatory T-cell (Treg) depletion to study immune-mediated preterm birth. She explores how maternal immune tolerance shapes the in utero environment and the developing neonatal immune system, with a focus on IL-9 and STAT3 signaling and the uniquely rule-breaking immunology of the placenta. The conversation also turns to mentorship and community, including the Pediatric Scientist Development Program, and closes with what keeps Dr. Lajiness grounded outside the lab: rock climbing with her family.

Link to episode on youtube: https://youtu.be/zqudpksfjxE

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The transcript of today's episode can be found below 👇

Ben Fensterheim (00:01.922)

Hi everyone, welcome to another episode of The Incubator: At the Bench. I'm really excited for our interview today with Dr. Jackie Lajiness. My name is Ben Fensterheim — I'm an instructor in neonatology at Children's Hospital of Philadelphia. I'm going to pass it over to my co-host, David.

David McCulley (00:23.869)

Thank you, Ben. My name's David McCulley. I'm a neonatologist and a physician-scientist at the University of California, San Diego. I study the developmental biology of the lung and pulmonary vascular development. I'm also very excited to be co-hosting this episode and talking with our guest, Jackie Lajiness, from Indiana University. I met Jackie through the Midwest Society for Pediatric Research, and it sounds like she's helping host that meeting coming up in Indianapolis next month. We're excited to talk with you today, Jackie, and to hear about your work and ask about how your career got started. But first, so our audience knows more about you — would you mind saying who you are, what career stage you're in, and giving a brief introduction to the type of work you do?

Jackie Lajiness (01:20.582)

Of course — thank you, David and Ben, for having me on. I'm so excited to be here. I'm a neonatologist and physician-scientist at Indiana University. I started my lab right after fellowship, so about three years ago. Now I'm an assistant professor, and my lab looks at how the maternal immune system can contribute to preterm birth, how that affects the in utero environment, and what effect that has on the development of the neonatal immune system.

David McCulley (01:55.955)

That's perfect, thanks Jackie. To begin, can you talk about what motivated you to study this line of research? It's something we all wonder about — what causes preterm birth — but it's exciting to think about it the way you have, using basic research to try to understand it.

Jackie Lajiness (02:18.3)

Sure — I was surprised at how much there still is to learn about what causes preterm birth. Of course, no one thinks it's one mechanism; there are lots of things that lead to preterm birth. But I was particularly interested in this subset of moms who are otherwise healthy — there's no overwhelming infection, they don't have severe preeclampsia putting mom and baby at risk — but they're still going into preterm birth. My thought was, if we understood more about the mechanisms, and potentially how mom's immune system is creating this inflammatory environment that starts the process of labor and delivery, could we first identify those moms, and second, intervene in a way that would help both mom and baby and improve outcomes? That's kind of where I got started.

Ben Fensterheim (03:18.21)

Yeah, I think that's fascinating — it sounds like what happens before birth extends not just to delivery itself, but to life after birth, to neonatal life, maybe life in the NICU (Neonatal Intensive Care Unit) or life at home later. How have you been able to study such a broad topic? Where do you find the areas of focus in studying immune development from maternal to neonatal life?

Jackie Lajiness (03:55.871)

It is a pretty broad topic. Right now I work on preclinical models — I have a mouse model where we deplete T regulatory cells (Tregs). We know that in humans, moms who deliver preterm without other complications tend to have fewer Tregs, and the Tregs they do have don't function as well. So it's a model of loss of tolerance. I isolated that in a mouse model: I deplete Tregs in the third week of a mouse pregnancy, because if you do it earlier, you lose all the pups. Working with that model, I found that yes, the mice deliver preterm, and there are definitely changes to the mom's immune system. One of the things I look at is cytokine signaling, and IL-9 (interleukin-9) is something I've become interested in.

But in addition to the changes happening in mom, I think we're starting, as a research community, to understand and become more interested in how the fetus interacts with the in utero environment as well. So I also look at what changes are happening in the fetal liver during this time, because some of those cytokines cross the placenta, or there are other signaling factors that go from mom to baby and can influence development. My fellowship work looked at how neonatal dendritic cells change when the mom has allergies — just being in that in utero environment primes those dendritic cells for changes postnatally and predisposes them to developing allergy. So I started looking at the same kind of process in this model of preterm birth, and I do find changes in gene expression, as well as in the profile of immune cells in the fetal liver, that I can see as early as embryonic day 16.5. My next focus will be on what that actually means for the pups that are born early with those changes, and what functional relevance that has.

David McCulley (06:08.742)

That's great, Jackie, and it has huge implications — still very broad, but amazing that you're able to do this work and understand these mechanisms in more detail. Before we get deeper into it, since I think we both have a lot of questions, can we talk a bit more about your background and training and how you got to the position you're in now? Where did you learn about—

Ben Fensterheim (06:09.218)

Yeah, amazing.

David McCulley (06:37.584)

—the possibility of doing physician-scientist work? I know you have a PhD — how did you pursue that path? Could you talk about that a bit?

Jackie Lajiness (06:48.146)

Of course. I first started doing research as an undergrad — I came in as a self-appointed pre-med student at Hope College, a small liberal arts school in Michigan. Pretty soon after starting, people were telling me that doing research looks good on a med school application, so I figured I could do that. As a freshman, I went to the—

David McCulley (07:11.676)

Mm-hmm.

Jackie Lajiness (07:17.778)

—the handy-dandy website listing Hope's researchers, and found that one of my chemistry professors, Dr. Krieger, had a lab that worked on laser spectroscopy. I reached out to him and started working in his lab, alongside a bunch of other phenomenal students — we were all undergrads, and no one knew much about laser spectroscopy at that level, so I wasn't at a disadvantage. I lucked out — Brent was a phenomenal teacher. He loved building lasers and teaching, and I really enjoyed learning how to build a laser. That was cool, but what I really fell in love with was the intricacies of experimental design — being able to control the variables you can control, understand what you can't, and have the freedom to ask a question and actually go find the answer by designing an experiment that lets you do that. I really enjoyed my time there.

David McCulley (08:23.857)

Yes.

Jackie Lajiness (08:41.366)

And not only did I get to work with great people, I also got to present my research at conferences. I went to a few national conferences, applied for a grant — which was great — and fortuitously ended up sitting next to a professor from Case Western on a flight to one of them. She clocked me pretty quickly, because of course I was carrying that telltale poster tube — you know exactly what I'm talking about. We started chatting; she asked about my research and my career goals, and I told her I wanted to go to med school. She said, "Well, why can't you do both?" I remember thinking, wow, that sounds really intimidating — how could you possibly be good at both? — but realizing I couldn't say that out loud. That was the moment that planted the seed for the idea of a physician-scientist career path.

David McCulley (09:43.197)

Wow, that's amazing. That interaction with your mentor as an undergrad sounds really important — getting to see someone who's built this kind of career, doing research, asking questions, designing an experiment to test a hypothesis, and controlling variables so the conclusions are justified. And there's also a bit of chance involved — you happened to meet that person, and that conversation on your flight was also a bit by chance. But those things can be so meaningful. If you connect with people at an early stage, even if it doesn't feel that influential at the time, it can have a big impact on someone's thinking and open doors for what they'd consider for the future. So then I take it you learned more about the MD-PhD (Doctor of Medicine–Doctor of Philosophy) path and applied that route? How did that go?

Jackie Lajiness (10:52.058)

Yeah — I had some friends who'd already gone to medical school, and we'd talk about how it was going. They'd say how much they liked taking care of patients, but at some point you run up against questions with no answer, and as someone purely in clinical care you don't have much recourse to address those or improve the future quality of life for your patients. That really meant a lot to me, and I started thinking more seriously about the very long career trajectory that is the MD-PhD. When I applied to medical schools, I applied only to combined-degree programs. I met a lot of wonderful people through the interview process and saw how people who'd started careers as physician-scientists made it work. Wade Clapp was the director of the MD-PhD program at Indiana at the time, and he's a tremendous example, personally, of what it means to be a physician-scientist — one of the most genuine people, so excited about science and willing to mentor people. He was a big part of why I ended up at Indiana and why I've stayed here for my career since. So yeah, a lot of these things come down to chance, but you take the opportunities and run with them.

David McCulley (12:35.826)

Sure.

Ben Fensterheim (12:37.006)

Yeah, one of the things I love about this story is that it sounds like you approached the career from almost a conceptual love — you loved the idea of discovery, of solving problems, doing experiments, collecting data, and setting up controls, rather than the way some people approach it: "I really want to discover the answer to this specific problem because my mentor happened to be working on it, and I found it interesting." I think that's a great signal that you'll really love this path if you just love answering questions and doing experiments — and that's always going to be there in the career. I love that part of the story.

So, I'm curious — thinking about my own experience too — when you transitioned to finally becoming an MD-PhD student, how did you find that transition from your undergraduate physics lab to medical school and graduate school at the same time? Was it surprising, or what you expected?

Jackie Lajiness (14:00.894)

I'm not sure I had a lot of preconceived notions about that, since I'd never worked with cell culture or animal models — I approached it knowing I'd be learning a lot of new things, with a steep learning curve. But once I started medical school, I gravitated toward embryology and developmental biology, and that became my focus in choosing labs. I ended up in a cardiac development lab, and I really enjoyed the science — learning about and working with transgenic mouse models. I won't lie, we did timed matings, because we were studying embryonic development. The first time someone said, "just go check that mouse for plugs," I thought, excuse me? What do you mean? Definitely a steep learning curve — but those are things I still use in my research today. I work with transgenic mouse models, I do timed matings, and I like that developmental angle, which has been a continuing theme throughout my work.

David McCulley (14:59.698)

What exactly does that mean?

Ben Fensterheim (15:00.59)

Yeah.

Jackie Lajiness (15:23.23)

Anyway — I took those experiences, and as I became more refined in my clinical interests, I knew I wanted to move toward how maternal health affects the health of the baby, and how the timing of pregnancy can be a really critical window for some of these changes. When I was in fellowship, I was able to identify Joan Cook-Mills as a research mentor — she had a model of maternal allergy and neonatal allergic predisposition, and we worked together on a project where I learned a lot about immunology, specifically the innate immune system. I also learned skills like flow cytometry that I'd never used before, and I knew that was the direction I wanted to take my lab. I learned a lot from that experience, and now I do immunology research — I'm still working on identifying as an immunologist, and I feel like I still have a lot to learn, but Mark Kaplan is one of my mentors, and he's just a great T-cell biologist, so I'm still learning a lot. Now I use spectral flow cytometry, so I feel like I've come full circle — I'm thinking about excitation and emission spectra again, just like back in the laser lab.

David McCulley (17:00.042)

That's perfect. Can we talk briefly about your timeline? I think one of the issues these days is how to keep people on this track interested, motivated, and engaged, given the real challenges of clinical training. When you finished your MD-PhD and started residency, did you have much opportunity to stay in a lab or keep doing research, or—

Ben Fensterheim (17:04.255)

Yeah, wow.

David McCulley (17:32.55)

—was it something you felt you basically had to put on hold, knowing you'd get back to it, hopefully as a fellow?

Jackie Lajiness (17:38.015)

That's a great question. For me, I knew I wanted to take a bit of a different approach to my fellowship work, so for residency I did not do an accelerated or integrated research pathway. Part of the reason was that I had my first child in medical school, so as a resident I had an infant at home, and I knew I wanted to leave space for everything I'd be learning clinically in residency. So I took month-at-a-time opportunities where I'd go into a lab and focus on a single technique. I learned—

David McCulley (18:20.359)

Yeah.

Jackie Lajiness (18:25.166)

—I went and learned CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) gene editing — did a short experiment in Laura Haneline's lab, worked with CRISPR just to learn the technique, and did some in vitro studies, things I hadn't done much of in graduate school. I used that time to identify techniques or areas of weakness I wanted to eventually incorporate into my own work. Then I applied for the PSDP, the Pediatric Scientist Development Program, which supported my fellowship research and gave me two years of protected time at the end of fellowship — which I thought was critical for transitioning into having my own lab right out of fellowship. That was the trade-off and the sequence I followed: I came out of fellowship, started as a tenure-track assistant professor on a K12 (NIH Institutional Research Career Development Award), and worked toward establishing my own research program, generating preliminary data, and applying for a K08 (NIH Mentored Clinical Scientist Research Career Development Award). That's been my trajectory in the first few years since fellowship.

David McCulley (19:53.619)

That's perfect, Jackie, and really helpful for people to hear. I think a lot of people find it challenging to use any time during residency for research skill development — it can feel fragmented — but I like that you sought out specific opportunities to learn a specific technique. And I think talking about the PSDP, and how much it can help people have a solid mentor relationship and a sense of support that this career path is one they can keep making progress on through fellowship and into early faculty years, is really great. Can we start talking more about your science now? I think Ben and I both have a lot of questions about that — is that okay?

Jackie Lajiness (20:49.416)

Sure.

David McCulley (20:51.398)

Do you want to start, Ben, or — what questions are you most focused on right now, Jackie?

Jackie Lajiness (20:56.51)

Right now I'm focusing on the model of Treg depletion during pregnancy — if Tregs aren't acting the way they should during pregnancy, what are the changes that predispose to preterm birth? That's probably what my K award is focused on. And then something that's grown out of that, which I see as a future direction I'll start to grow, is some of the changes that—

Ben Fensterheim (21:08.258)

Yeah. Mm-hmm.

Jackie Lajiness (21:25.63)

—happen in the neonatal immune system developing in that environment.

Ben Fensterheim (21:33.983)

I've struggled to be considered an immunologist myself, but I'll slowly try and pretend. Treg dysfunction — it sounds like something you're inducing in some way in the mom, or the dam? Is that right? So what type of exposures during pregnancy might cause—

David McCulley (21:39.192)

[laughs]

Jackie Lajiness (21:53.567)

Yes — right on all counts.

Ben Fensterheim (22:03.766)

—Treg dysfunction the way you're inducing it in mice?

Jackie Lajiness (22:08.69)

The mouse model is a little artificial, because we use a FOXP3-DTR (forkhead box P3–diphtheria toxin receptor) model — these mice have basically a suicide receptor on all their Tregs, so I can induce depletion by giving them diphtheria toxin during pregnancy. Mice don't normally express the diphtheria toxin receptor on any of their other cells, so it doesn't cause problems elsewhere in mom — it just selectively depletes the Tregs. So it is a little artificial, because that's not what happens in human pregnancy. Typically, what we see is a pretty big expansion of regulatory T cells during pregnancy, and the idea is that those cells dampen the immune response so mom can tolerate this allogeneic fetus growing inside her. We don't really know if that initial response is lower in moms who go on to deliver preterm, but people have shown that, at least once symptoms start, the amount of circulating regulatory T cells in the blood is predictive of how soon a mom will deliver — moms with lower numbers of regulatory T cells are more likely to deliver within the next 48 hours, and a couple of studies have shown that. And if you look at the time of birth, and look in the decidua of those placentas, you find that regulatory T cells isolated from the decidua are not as good at dampening T-effector-cell responses in placentas from preterm deliveries, compared to those delivered at term after going through labor.

So it is a bit artificial, but it lets us evaluate something we can't do in human pregnancies — we get rid of the Tregs and ask, what's happening two days after that, three days after that, before birth occurs, before the labor process starts — what are the changes that ultimately lead to that process? There's no perfect animal model, but I like this one because, one, it's immune-mediated preterm birth — we're identifying a pathology that, if we could intervene on it in humans, would actually be helpful. There are times when the baby just needs to be delivered for mom's or baby's health, but in this case, if we can stop that loss of tolerance, or something close along that pathway, can we actually prolong gestation and keep that baby in a healthy in utero environment for longer?

Ben Fensterheim (25:17.58)

Yeah, I think it's fantastic, because inflammation has been associated with preterm birth in many different contexts, and this focuses on one of the most important cell types in regulating inflammation — how they change observationally, and then how changing them experimentally can induce something like preterm birth. I think it's a great way to explore the role of these cells in general inflammation, and whether a generalized inflammatory event can precipitate preterm birth. I completely agree about the practical utility of studying the immune system, since there are so many potential targets to address what's going on.

I'm also curious to hear more — you mentioned that right around the time of birth, these cells change their function, maybe their location or phenotype: they decrease in the blood and change their function in the placenta and uterus. In your experiments, have you found what might cause these cells to change during pregnancy? I'm asking because I know many parts of the immune system change during pregnancy simply because of pregnancy — do Tregs, or other inflammatory mediators, change just because of pregnancy, or because of delivery itself?

Jackie Lajiness (26:59.826)

Great question — a lot of people are still working on defining the dynamic nature of the immune system throughout gestation. But yes, Tregs increase basically right after conception, and then start to tail off before the natural onset of labor and delivery. We don't really understand the mechanism of how that happens in humans, or why — what signal are they responding to? A maternal signal, a fetal signal, some interaction between the two? There's still a lot we don't know about what starts the labor and delivery process in humans, which is important, especially for us as neonatologists — we really care why this is happening.

David McCulley (27:57.575)

That's great, Jackie. I was wondering, just very simply, since we'll have a pretty broad audience — in your model, do the mice actually deliver early?

Jackie Lajiness (28:09.564)

Yes, the mice deliver early — not all of them, but it shortens the gestational duration overall. If you arbitrarily define preterm birth as embryonic day 18.5 (E18.5), only about 20% of them deliver before that point. But if you graph it out, it definitely shifts everything — they're delivering about a day to a day and a half earlier than a normal pregnancy.

David McCulley (28:36.976)

And it sounds like you're studying both the pups and the placenta — is that right?

Jackie Lajiness (28:43.75)

Yes, most of my work has focused on the placenta as well as the fetal liver — the pup response as well.

David McCulley (28:51.676)

Because you're reducing immune tolerance, what do you see in the placenta? Evidence of an inflammatory reaction? Or does the loss of tolerance mean the placenta isn't growing well, or failing early? What do you find?

Jackie Lajiness (29:17.202)

The placentas aren't smaller or anything like that — I'm still working through some histology, but people who've published this model before haven't shown huge changes in placental structure, so you're not damaging the placenta in an obviously dramatic way. Nardhy Gomez-Lopez has even done ultrasound evaluation showing that blood—

David McCulley (29:38.562)

Interesting.

Jackie Lajiness (29:46.575)

—flow through the placenta is intact, and the pups themselves are the same weight, so I don't see a big IUGR (intrauterine growth restriction) phenotype. Overall, it seems like a fairly healthy pregnancy. I've looked at the expression of certain inflammation-related genes — I mentioned IL-9 signaling has been something I've found interesting.

David McCulley (29:48.142)

Wow.

Jackie Lajiness (30:13.742)

The NLRP3 (NOD-like receptor protein 3) inflammasome, which has been studied a lot in preterm birth research, can actually be downstream of IL-9 signaling, and it's also increased in the placentas and fetal livers of these mice. So there are definitely some gene targets there. I'm working toward doing more single-cell-focused work so I can see which cell lineages are contributing which changes, and understand the mechanism a bit better that way. That's the direction I'm moving.

Ben Fensterheim (30:50.166)

I'm curious about the pups that are born — even though they seem to be normal weight, and it sounds like the only thing that's really changed observationally about the pregnancy is the timing of delivery in this model — do you see changes later in the pups' immune system, or their growth and development after birth?

David McCulley (30:50.514)

Perfect.

Jackie Lajiness (31:14.754)

Growth and development seem fairly normal — I follow them through weaning, up until they're three to four weeks old, and their growth trajectory seems normal. I'm working on time points to actually look at their immune composition postnatally. Most of what I've done so far has been right around the time of birth or during gestation, but I do see changes I want to follow longitudinally — that's still to be done.

Ben Fensterheim (31:45.815)

Amazing — well, I'm biased in my interest there, as someone who studies preterm infant immune development, but fascinating. Sorry, I think I jumped in on you there, David.

David McCulley (31:58.341)

No, not at all — I was trying to keep it in the clinical realm a bit, because a lot of times, if a woman comes in with threatened preterm labor, one of the first things we recommend as neonatologists is betamethasone. It seems like, in addition to helping mature lung function, it also acts to decrease inflammation. Have you tried that in your model — depleting the Tregs in mom and then giving steroids, to see how that affects the risk of delivering prematurely and the inflammatory reaction? Or what do you think?

Jackie Lajiness (32:38.111)

That's a great question — I haven't done that in our model yet, but it's something we think about. There's so much about caring for inflammation that plays into how we take care of preterm babies and think about their comorbidities. If you're talking about NEC (necrotizing enterocolitis) or BPD (bronchopulmonary dysplasia), how that infant experiences inflammation definitely changes the course and severity of the disease — it's a really big modifying factor. You can have babies exposed to what we think of as the same stimuli, but with very different courses and outcomes, and that's one of the fascinating things we see as clinicians. It's a really hard part of taking care of babies in the NICU — we can't always predict. But if we can understand whether a baby's immune system is primed to react a certain way based on their in utero environment, can we get better at predicting, or tailor our treatments postnatally to help them through the milestones they have to face? That would be the gold standard for what I'd like to contribute — if we can understand a bit better how to approach and care for our babies, we might be able to improve their outcomes.

David McCulley (34:17.916)

That's exactly the question I was wondering about. I remember talking about this with Ben regarding his work — we often talk about steroids in the NICU for preterm delivery, but also in preterm infants with severe lung disease. The whole idea is to decrease the inflammatory reaction, but it does so through so many mechanisms we don't completely understand. So trying to understand the actual mechanism of how depleted immune tolerance leads to preterm birth might point to a specific pathway — and steroids might be effective there, but maybe there's something more specific that avoids the potential downsides of giving betamethasone. That's great, so—

Ben Fensterheim (35:11.086)

Go for it — no, no, please. I wasn't going to ask another question, I was just going to continue your comment, because I think it's such a good point. Anytime you see an anti-inflammatory antibody or a very specific molecule being used, you can bet that in that disease they tried steroids first.

David McCulley (35:12.742)

Go ahead, Ben.

Ben Fensterheim (35:40.795)

And the targeted therapy was better — almost across the board in rheumatologic disease, there are examples from oncology, GI — steroids are often the first thing tried when you've identified an inflammatory event, but in so many cases, getting specific with the anti-inflammatory intervention improves the therapeutic effect. That's why I love how you're anchoring on Tregs as the mechanistic cell here, because they can be targeted specifically, and the cytokines they make can be targeted too. It does raise the question — maybe we should be giving not just betamethasone for the lungs, but also an anti-inflammatory to try to slow the preterm birth itself.

Jackie Lajiness (36:41.949)

Not to get too much into the weeds, but it's really interesting to think about how much context matters. A single cytokine never acts in isolation — it can change the whole immune environment. Cytokines can change receptor expression, and they can change expression levels of transcription factors, which then mediate those effects. So take a stimulus like LPS (lipopolysaccharide) — we know LPS exists at low levels even in healthy pregnancies. But if you're changing the immune environment to make it more sensitive to detecting and responding to LPS, are you changing the tolerance threshold for what that small stimulus does? Does that mean that in a mom with an inflammatory milieu, that same low level of LPS could tip her over the edge toward preterm labor and delivery, just because of the immune context — whereas another mom could tolerate that same level of LPS with no effect? I think that's what makes the mechanism so interesting to me: the more we understand about context, the more targeted we can be with our approaches, like you were saying, Ben — is there a better target to hit that gives us the benefit without some of the side effects?

David McCulley (38:23.95)

Is IL-9 something you're thinking about as a target? Is that one of the things where, if you blocked it, you might be able to reduce the risk of preterm delivery? What were you thinking there?

Jackie Lajiness (38:36.137)

I think it's a very interesting target, because it's been shown to lead to preterm delivery — it signals through STAT3 (signal transducer and activator of transcription 3). So those are the mechanisms I've focused on, IL-9 and STAT3, because STAT3 also signals downstream of IL-6 (interleukin-6) and of TLRs (Toll-like receptors) that respond to LPS. That's the signaling pathway I'm focused on right now. But it's important to remember that all of this exists in the context of a lot of other cell types, and not losing sight of that is important — so that's how I'm trying to focus my research: learn the mechanism, but always keep in mind it exists in a larger context.

David McCulley (39:31.578)

Everything in balance.

Ben Fensterheim (39:33.347)

I'm wondering — because you're talking about specific cells and cytokines associated with preterm labor and delivery, but there are other maternal reasons for needing delivery, like preeclampsia or infection. Do you find there are different immune factors associated with something like preeclampsia—

Jackie Lajiness (39:35.681)

At least trying to, right?

David McCulley (39:35.099)

Yeah.

Ben Fensterheim (40:02.43)

—compared to something like preterm labor?

Jackie Lajiness (40:05.919)

I think that's really important to keep in mind — yes, they're probably very disparate mechanisms. The reason I've focused on immune-mediated preterm birth is that we can intervene there without hurting mom or baby. With preeclampsia, mom is having a life-threatening reaction, and if the baby isn't delivered, it's going to cause problems for both — the placenta isn't healthy at that point. So while it's valuable to understand that mechanism too, preventing the preterm birth might not actually be the best thing for mom and baby in that context. That's why I'm trying to focus on the population of moms I think could benefit most — from actually stopping that process without negative consequences for either of them.

David McCulley (41:10.03)

Since you're thinking along those lines — to identify a pregnancy that would be at risk, are you thinking about quantifying regulatory T cells earlier in pregnancy, or even in women before they're pregnant? How would you go about identifying an at-risk pregnancy?

Jackie Lajiness (41:31.519)

I'd love to appreciate the dynamic nature of pregnancy and start by looking at how regulatory T cells change throughout — moms don't necessarily get frequent lab draws, but there have been some studies looking at circulating Treg levels, though they usually don't start until mom comes in with contractions or is noted to have cervical dilation on an exam.

David McCulley (41:36.689)

Yes.

Jackie Lajiness (42:01.396)

So I think starting earlier in pregnancy and understanding better how that changes is key. Is it that moms at risk for preterm birth have less of an expansion of their Tregs from the get-go, and that low level is just maintained? Or do they have the normal expansion, but it starts to tail off a bit earlier, leaving them more vulnerable because it reaches a critical threshold earlier in gestation than in other people? I don't think we have a great answer yet, but there are a lot of people doing amazing work on these same questions, and I'd like to be part of that — I think it's important work.

David McCulley (42:48.694)

You also mentioned function — even if the number is normal, but they're not functioning normally. Are there good assays for testing regulatory T cell function? How do you evaluate that immune tolerance is lost due to function, even when the number is normal?

Jackie Lajiness (43:08.121)

Most people — Nardhy Gomez-Lopez has published some of this work — isolate effector T cells and Tregs from the decidua, and then do dilutions: fewer and fewer Tregs, to see how effectively they can suppress the T-effector cells. It's almost like an antibody titration — they find the lowest effective dose, which tells you how effective the Tregs are at inhibiting that response. That's how the work has been done so far.

Ben Fensterheim (43:53.583)

Do you think most of the Treg's effect is canonical — suppressing the inflammatory activity of other cells the way you'd typically think of a Treg, by secreting cytokines or directly interacting with other cells? Or might there be a more unusual role for these cells in the placenta and uterus? I'm—

David McCulley (43:53.594)

That's great.

Ben Fensterheim (44:22.168)

—thinking of a colleague who studies NK (natural killer) cells in the uterus and placenta — they have a very unique function there that they don't have in more canonical settings. Does the Treg have anything like that? Are there any unique activities of Tregs in pregnancy?

Jackie Lajiness (44:43.909)

That's a great question — thank you for giving me one more thing to think about. I haven't come across a description of a very pregnancy-specific Treg function, but it's possible — Tregs respond to progesterone and other hormonal cues, and they don't just secrete their own cytokines, they also—

David McCulley (44:48.06)

Yeah.

Jackie Lajiness (45:13.063)

—act as a sink for things like IL-2 (interleukin-2), inhibiting growth factors available to other cell lines in that context. The environment in the placenta, we have to assume, is very different from how things work in peripheral blood, so I wouldn't be surprised if there's something unique there — but that's not something I know is well described at this point.

Ben Fensterheim (45:41.512)

Fascinating — it feels like a whole unique world, the placenta especially, but the uterus too.

Jackie Lajiness (45:51.667)

Well, that's why a lot of people say they want nothing to do with the placenta.

Ben Fensterheim (45:56.495)

Is that right? Because it messes up all the other experiments or something?

Jackie Lajiness (46:02.431)

Because everything's just different. It has its own rules.

Ben Fensterheim (46:05.857)

Yeah.

David McCulley (46:08.346)

I think that's why it's so interesting — obviously it's so necessary for our survival, but it's complicated; there are so many systems that have to be in balance for it to work normally, and if they're just subtly perturbed, things can go really wrong. It's one of those examples where it's amazing it ever works at all. Since I'm a developmental biologist, I always think—

Ben Fensterheim (46:08.482)

Yeah.

Jackie Lajiness (46:30.548)

Yeah.

David McCulley (46:35.462)

—the way you study the function of something is to knock it out, so you're reducing the function of the Tregs, and that helps in one way. What happens if you turn them up? If you have too many, or overactivate their function, how does that affect things? Do you know anything about that — is that an issue?

Jackie Lajiness (46:56.102)

Great question — I don't know that we have a functionally relevant model in human disease, and I'm not sure there's a great mouse model of that either. Do you know of anything?

David McCulley (47:11.034)

That's totally outside my world, I don't know. I was just wondering — that's how we tend to think about pathways: if you remove it, you see what happens; if you overactivate it, or activate it in a context it's not normally in, what happens? I was wondering, especially thinking about whether—

Ben Fensterheim (47:33.038)

Yeah, I don't—

David McCulley (47:37.04)

—to build on Ben's question — is it a canonical issue, where if you're just maintaining a balance of immunoregulation and you turn it up too far, the animal becomes susceptible to infection, or to things you'd want some inflammatory response to?

Jackie Lajiness (47:56.102)

Right — that's part of the perfect balance pregnancy needs: enough Tregs to dampen the immune system so the baby can grow and flourish, but not so much that mom becomes immunocompromised and the whole pregnancy is put at risk. Good point.

David McCulley (48:20.634)

I think you're on a really interesting track.

Ben Fensterheim (48:20.738)

Yeah, I wonder if there's a way to induce FOXP3 expression in some of your models, to skew CD4+ (helper) T cells into becoming more Tregs — but that's probably another piece to add to the genetic soup of the mouse. Fascinating.

David McCulley (48:48.259)

Thank you, Jackie, that was really excellent — you're an amazing teacher. I'm not an immunologist, even less than either of you, and I feel like I learned a lot and could easily see how this applies to such a common problem — preterm birth is the most common reason babies are admitted to the NICU we take care of. It's fascinating to think about the many ways preterm birth can happen, and how we can learn from our patients and design experiments to study the things we encounter all the time.

Before we finish, since you mentioned the PSDP was really helpful in getting your career established, could you talk a bit more about that, or other programs you've been part of that helped develop your physician-scientist career? That's something we're really interested in — how we enable more people to pursue this path — and hearing about experiences like yours is really helpful.

Jackie Lajiness (49:50.816)

The PSDP is a program built by the AMSPDC (Association of Medical School Pediatric Department Chairs) and supported by the NIH — I know there's a lot of uncertainty right now about how that funding works, but here's what it is: you apply either in your last year of residency, for most people, or your first year of fellowship if you're in a critical care specialty. I applied in my first year of fellowship, since I was a neonatology fellow, and it provides two years of protected research time at the end of fellowship.

Beyond that protected time, I also got to meet other pediatric scientists at a similar career stage

, all aiming to eventually run their own labs, and that really built a community. We still have a group chat where we check in — I just got an update the other day that one of the guys' wife had another baby. We keep in touch, whether it's someone submitting a K08 or a K23 (NIH Mentored Patient-Oriented Research Career Development Award), or moving institutions and setting up a lab, hiring a first technician. That community has been huge for me — the path is hard, and there are times it gets rough, but having a group of people to reach out to and go through it together makes a big difference. The PSDP was wonderful both for the research support and for that community, and I think that's probably been its biggest impact for me.

There have been other helpful programs too. As faculty, I was on a K12 here at Indiana, and having the support of your chair and division chief — I don't think you can do research without that — has been instrumental. And smaller things, like the Perinatal Research Society's grant-writing course — I did that my first year as faculty, working on my K08 submission, and met a bunch of great people at a similar career stage, and got feedback from people outside my own institution. I think building community and networking through opportunities like that has probably given me the most staying power in a career that can, at times, feel quite uncertain.

David McCulley (53:10)

How did you get introduced to those different programs? With the PSDP, for example, had you heard about it before, or how did that come about?

Jackie Lajiness (53:17)

People I did my MD-PhD with, who were a couple years ahead of me and went into pediatrics — Simon Rhodes, who's a PhD, was a couple years ahead of me, and it's something he'd done. From the get-go he said, this is a great program. And Wade Clapp, my chair, was also really big on supporting the PSDP. So between those two influences, I knew it was going to be on my trajectory to apply for. A lot of it's about the people — networking, and having people who look out for you and say, "hey, keep this on your radar, Jackie, this is going to be important for you." A lot of the time, they're right.

David McCulley (54:08)

PRS, the Perinatal Research Society, is a perfect environment for the work you do especially. I love the overlapping, cycling leadership — there's a neonatology group, a maternal-fetal medicine group, and a basic research group, and leadership and the meeting's focus cycle through those three. That grant-writing course, like you said, I thought was outstanding — I brought an Aims page, and sat with someone, I think it was Kurt Albertine, who read it and gave me feedback. I went to another room, edited it, brought it back to him, again and again. It really felt like I made a lot of progress, and you also get other advice and another chance to network with people at a similar career stage, like you said.

Jackie Lajiness (55:00)

I had a very similar experience — I love that meeting, and I'm actually going back this year to present my work in one of their short sessions, so I'm excited about that. It's a small enough meeting that you can actually talk to everyone, and I really appreciated that, especially as someone breaking into the reproductive immunology space — that was a newer area for me as I started establishing my lab as faculty. It's great to meet key people in that setting and get great advice on grant writing in general.

David McCulley (55:47)

Perfect, thanks Jackie, that was excellent. We're pro—

Ben Fensterheim (55:50)

I also wanted to ask about Indiana, because in the few interviews I've done so far, two have been with up-and-coming, successful physician-scientists at Indiana — Hugh, and Kristen Noble. I have to think there's something special going on there, and I'm curious—

Jackie Lajiness (56:00.96)

I was going to say Kristen Noble.

Ben Fensterheim (56:11.678)

—if that's true, and if so, what you think might be the keys to success in your environment at Indiana?

Jackie Lajiness (56:19)

I very much think that's true — Riley is a very special place, and one of the people I credit for that is Wade Clapp. He was the MD-PhD program director when I came on, and he's been chair of pediatrics here for as long as I can remember — he just stepped down this year and passed the torch. Between him and Laura Haneline, our division chief of neonatology, who also has a background as a physician-scientist, the way they buy in and support people is incredible. Wade was on my scholarship oversight committee as a fellow, and I remember after one of my presentations he came up to me and said, "Jackie, you're doing really cool stuff, I'm excited for you" — and, "I've got your sign-on package ready for when you're faculty. I want you to interview everywhere, but I'm going to make you the best offer, and I'm going to keep you here at Indiana." And he was right.

Ben Fensterheim (57:24)

Wow, that's amazing.

David McCulley (57:27)

Great to have your chair in your corner like that early on. That's awesome.

Jackie Lajiness (57:32)

It doesn't get much better than that. Really, that kind of support — you don't get it everywhere — and that investment in you as an individual and in your science is pretty special.

David McCulley (57:50)

It seems like it's really been a good program, helping you develop the skills to build a really exciting research program — addressing a common problem we don't understand very well, using techniques that can really get at the underlying mechanisms and help us learn and make progress. Super exciting. We're probably near the end — we usually finish by asking something that shows we don't spend all our time in the lab. Jackie, is there anything you like to do, personally, as a research group, or with your family, outside of work?

Jackie Lajiness (58:48)

With my family, we like to go rock climbing — a lot of times indoors, though I haven't quite taken my girls out to Red River Gorge yet, but I've climbed there myself, so I enjoy that. As a research community, my lab is really small right now — just me and a technician — but we exist within the Kaplan lab sphere, so we'll go out to meals occasionally, or when we're at conferences together.

Actually, a quick anecdote: PAS, the Pediatric Academic Societies meeting, the big pediatric research conference, is usually in the same city as AAI, the American Association of Immunologists meeting, the big immunology research conference — but they're usually about two weeks apart, close enough that I never go to both in the same year. Last year I went to PAS, and it happened to be in the same convention center where AAI would be held two weeks later. So I took a little Post-it note, wrote the lab a message, stuck it on a wall in the convention center, and took a picture — just to see if it would still be there when they were there a couple weeks later. They went on a little scavenger hunt, found it, took a picture, and texted it back to me. It's a small thing, but it shows the kind of community and connection that can be so important in a research lab environment.

David McCulley (01:00:21)

Wow. I totally agree — that community is essential. Having a common bond and shared experience is so valuable; it makes the work much more interesting and exciting to do.

Jackie Lajiness (01:00:45)

Exactly.

Ben Fensterheim (01:00:49)

Awesome.

David McCulley (01:00:49)

Cool. Well, Jackie, thank you so much for taking the time to talk with us today — it was great to learn about your work and your motivations. You're a great role model, and it's awesome to hear how you got to where you are. We're excited to hear what you do next. One thing we didn't get to — the Midwest SPR meeting is coming up in just a couple of weeks, and I know you're involved in hosting it, which will be great, along with the career development session, where I'm sure you'll have a great influence on the people presenting there. But thank you so much for taking the time to talk with us today.

Jackie Lajiness (01:01:29)

Thanks for having me, I really appreciate it — I hope to see everyone in Indiana for the Midwest SPR!

David McCulley (01:01:35)

Awesome, thanks, Ben.

Ben Fensterheim (01:01:37)

Awesome, thanks, Jackie. Thanks, David.

Jackie Lajiness (01:01:39)

Thanks, everyone — appreciate it. Bye!

David McCulley (01:01:40)

Bye!