An interview with Kristen Pollizzi
In the May issue of the JCI , Pollizzi et al. provide new insights into how the mTOR pathway regulates CD8+ T cell effector function and memory commitment. Using a series of elegant mouse models, their work defines distinct roles for mTORC1 and mTORC2 signaling in controlling the metabolic programs required for CD8+ T cell differentiation. Constitutive activation or repression of mTORC1 activity disrupted CD8+ T cell effector function, whereas loss of mTORC2 promoted skewing toward CD8+ memory cell formation. We had the opportunity to talk with first author Kristen Pollizzi about this work, as well as her current research efforts.
Can you tell us a little about yourself?
I grew up in Baltimore, went to college at Boston College, and then attended graduate school at John Hopkins University School of Medicine, where I joined Jonathan Powell’s lab. After I received my PhD, I continued with a short postdoc to wrap up my work in the Powell lab, and I have recently transitioned to become a scientist at MedImmune, where I work on novel immunotherapies.
When did you start the work in this article?
This project has so many different layers to it, it’s hard to pin a specific start date. It probably started in 2010, which is kind of scary to admit. We just kept adding more information based on what we were finding along the way. When we saw something interesting in our mice, we added further genotypes and new experimental models, so the work kept evolving over time.
Given this evolution, did the project end up where you thought it would?
That’s an interesting question. There were some difficulties, because while I was working on the story, there were papers coming out on TSC1-deficient CD8+ T cells (1–6). My work focuses on TSC2, unlike the published reports. However, TSC1 and TSC2 form a protein complex that acts as a negative regulator of mTORC1 activity. Loss of either TSC1 or TSC2 results in the hyperactivation of mTORC1 signaling. We speculated that a Tsc1 knockout would resemble a Tsc2 knockout, but the data generated from the Tsc1 knockouts were fundamentally distinct from what we observed.
In the Tsc1 knockouts, the authors reported increased cellular death and reduced CD8+ T cell effector capacity, but in our hands with the Tsc2 knockouts, we found that the CD8+ T cells didn't die immediately. They actually had enhanced effector function and even better tumor clearance. We had to ask, “What is going on, why is this so different?” We discovered that even though these two genotypes would have been predicted to be similar, it looks like their signaling is distinct. We proved this idea after we generated a double-knockout mouse, which has loss of TSC2 and RICTOR [a component of mTORC2], and phenocopies the TSC1-deficient cells that the other reports have described.
Do you recall a particular moment when things suddenly became clearer?
When I finally saw the data with the double-knockout cells, that’s when I let out a huge sigh of relief. But each layer of discovery just kept building on the others. It started with the Tsc2 knockout, and then the Rheb knockouts, which have loss of mTORC1 activity. Their phenotypes matched in that one did the opposite of what the other would do, which helped me feel confident in my data. Each genotype and layer we added fit into the mold, and it just kept going little by little.
Is there anything in your work here that closes the book on any discrepancies that are out in the literature?
Yes, I believe so. There has been a flurry of manuscripts that have come out suggesting that there is a role for mTOR in CD8+ T cell function, but by utilizing these genetic knockouts, we could very specifically and distinctly prove exactly what signaling pathways are important for what function of the T cells. It is important to highlight the differences between mTORC1 and mTORC2 activity, because the differences between these pathways are often overlooked. Manuscripts will focus on the effects in one without mentioning the other. In addition, getting back to the TSC1 publications, the current published literature suggests that the hyperactivation of mTORC1 is detrimental to CD8+ T cell function. My data challenge this idea, but also demonstrate a reason for the discrepancy: hyperactivation of mTORC1 enhances CD8+ T cell effector function only in the presence of active mTORC2 signaling. Thus, this work provides further insight into the role of mTOR in CD8+ T cell function.
What things did you feel really contributed to having such a successful project as this?
A great mentor and a good communication with your mentor are both key. Additionally, I think a collaborative environment is critical for good science. I was very lucky to have amazing labmates who are incredibly hard working, but also a lot of fun. We truly worked as a team for many of the experiments in this paper, and they were pivotal to the success of this paper, so I definitely have them to thank for this.
What influenced you to move from academic medicine into industry?
I was very interested in being part of an organization where I could take my knowledge and my skill set and apply it to develop therapies that I could see go into patients and improve people’s lives. I think it’s exciting to see our work translate into a product that could be beneficial to someone else. That’s what really made me take this leap, to try a different route from academia.
If you asked me a year ago if this was the route I was going to take, I don’t know if I necessarily would have been able to tell you that that was true. To be honest, I think as scientists, we are trained to think that there's only one path for us, and that’s to stay in academia. That’s great for some of us, but there are other opportunities that are available. I had to think about what it is that I want in life and what I want to pursue, and I decided to give this a try. I’ve been very happy so far.
Is there anything in your career development that you would have changed, or that you would recommend to others?
I’m very happy with my scientific training. I was surrounded by great science at Hopkins. I felt welcome to ask questions and initiate discussions with the scientists around me. I was able to go to meetings and present my work and gain fresh perspectives. This path has not always been easy, but I don’t think there's anything that I would necessarily change. There was definitely some failure, but without that, I don’t think I would be where I am now.
Science is tough. To survive as a scientist you have to be tenacious and resilient. My advice is to have a level head and a critical eye, push through when times are tough, and always let the data speak for itself. As for career development, I would highly recommend going to conferences, especially smaller ones, because it is such a great way to network with other scientists as well as to gain insight into the latest scientific and technology breakthroughs. Lastly, always feel confident to ask questions and challenge ideas — that’s how scientific advancement occurs.
Has your move to industry been what you expected?
When you move into a company, you don’t necessarily know exactly what to expect. But I’m doing a lot of active science, and it’s very interesting and exciting. In a way, it has actually been better than I had expected. I have felt challenged, in a positive way, by the work, and I also feel like I have a voice to contribute to the development of therapies that can enhance the quality of life for other individuals. That idea is incredibly rewarding to me and motivates me to work hard.
I also don’t think the switch is so black and white. People often paint academia and industry as two completely separate entities, but in reality, they are not. Great science is great science; and as long as you’re pursuing interesting, forward-thinking research, it’s very much the same.
(1) O’Brien TF, et al. Regulation of T-cell survival and mitochondrial homeostasis by TSC1. Eur J Immunol. 2011;41(11):3361–3370.
(2) Yang K, Neale G, Green DR, He W, Chi H. The tumor suppressor Tsc1 enforces quiescence of naive T cells to promote immune homeostasis and function. Nat Immunol. 2011;12(9):888–897.
(3) Wu Q, et al. The tuberous sclerosis complex-mammalian target of rapamycin pathway maintains the quiescence and survival of naive T cells. J Immunol. 2011;187(3):1106–1112.
(4) Zhang L, et al. TSC1/2 signaling complex is essential for peripheral naïve CD8+ T cell survival and homeostasis in mice. PLOS One. 2011;187(3):1106–1112.
(5) Krishna S, Yang J, Wang H, Qiu Y, Zhong XP. Role of tumor suppressor TSC1 in regulating antigen-specific primary and memory CD8 T cell responses to bacterial infection. Infect Immun. 2014;82(7):3045–3057.
(6) Shrestha S, Yang K, Wei J, Karmaus PW, Neale G, Chi H. Tsc1 promotes the differentiation of memory CD8+ T cells via orchestrating the transcriptional and metabolic programs. Proc Natl Acad Sci U S A. 2014;111(41):14858–14863.
About the First Author
Kristen Pollizzi received her PhD in immunology from Johns Hopkins University for her work in the laboratory of Dr. Jonathan Powell. She is currently a scientist at MedImmune.
About the interviewers
Freddy T. Nguyen is an MD/PhD candidate at the University of Illinois at Urbana-Champaign. He is the founder of the American Physician Scientists Association and served on the Associate Member Council of the American Association for Cancer Research. His research interests currently lie at the intersection of biomedical optics and cancer research. He received his B.S. in chemistry and B.A. in mathematics from Rice University.
James M. Pauff, MD, PhD, is a Clinical Fellow in medical oncology at Vanderbilt University Medical Center. He has served as President and on the Board of Directors of the American Physician Scientists Association. His research interests are in molecular pathways of cancer and targeted therapeutics, and he is currently in the laboratory of Carlos Arteaga, where he studies mechanisms of resistance to compounds targeting the estrogen receptor in hormone-positive breast cancer. Dr. Pauff completed his internal medicine residency at Vanderbilt and received his M.D. and Ph.D. from the Ohio State University.
Related articles
Abstract
Activation of mTOR-dependent pathways regulates the specification and differentiation of CD4+ T effector cell subsets. Herein, we show that mTOR complex 1 (mTORC1) and mTORC2 have distinct roles in the generation of CD8+ T cell effector and memory populations. Evaluation of mice with a T cell–specific deletion of the gene encoding the negative regulator of mTORC1, tuberous sclerosis complex 2 (TSC2), resulted in the generation of highly glycolytic and potent effector CD8+ T cells; however, due to constitutive mTORC1 activation, these cells retained a terminally differentiated effector phenotype and were incapable of transitioning into a memory state. In contrast, CD8+ T cells deficient in mTORC1 activity due to loss of RAS homolog enriched in brain (RHEB) failed to differentiate into effector cells but retained memory characteristics, such as surface marker expression, a lower metabolic rate, and increased longevity. However, these RHEB-deficient memory-like T cells failed to generate recall responses as the result of metabolic defects. While mTORC1 influenced CD8+ T cell effector responses, mTORC2 activity regulated CD8+ T cell memory. mTORC2 inhibition resulted in metabolic reprogramming, which enhanced the generation of CD8+ memory cells. Overall, these results define specific roles for mTORC1 and mTORC2 that link metabolism and CD8+ T cell effector and memory generation and suggest that these functions have the potential to be targeted for enhancing vaccine efficacy and antitumor immunity.
Authors
Kristen N. Pollizzi, Chirag H. Patel, Im-Hong Sun, Min-Hee Oh, Adam T. Waickman, Jiayu Wen, Greg M. Delgoffe, Jonathan D. Powell
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