Memory T and B cells constitute our primary system of defense against reoccurring infectious disease, and the ability to form these cells is the ultimate goal of vaccination. My laboratory aims to understand how memory T cells are generated during infection and vaccination and why, in some circumstances, an immunization fails to induce long-term T cell immunity. We are also learning how T cells are regulated in tumor microenvironments to better understand how their functions become suppressed as they infiltrate tumors, to develop new methods of immunotherapy that enhance antitumor responses. We are using several powerful model systems of infection or cancer in mice to elucidate mechanisms involved in the development of protective and long-lived memory T cells that form after acute infection or conversely, of dysfunctional or "exhausted" T cells that form in tumors or during chronic viral infections. Our studies are aimed at identifying the signals and genetic pathways that regulate the differentiation of T cells in these different types of environments so that we can design new ways to optimize the formation of highly functional, protective memory T cells to fight infection and cancer.
What are the decisive factors that determine which effector cells survive to become long-lived memory cells and which cells die during the contraction phase?
We have characterized the transcriptome of effector and memory T cells and identified genetic pathways and several transcription factors that regulate this life-or-death decision in activated T cells. Our work has helped to outline a model of effector T cell differentiation wherein a small subset of T cells develop into memory precursor cells that are more fit to persist following the first infection than the majority of effector cells. These memory precursor cells develop into long-lived memory T cells that protect against reinfection. Several types of memory T cells, which differ by their phenotypes, functions, and anatomical locations, are produced to create a sophisticated, multilayered defense system. Conceptually, the memory T cells are divided into three subsets: (1) tissue-resident memory T (TRM) cells, which locally reside in mucosal tissues to provide the front line of defense against pathogens that breach our barriers; (2) effector memory T (TEM) cells, which circulate through the blood and tissues and are rapidly recruited to the sites of inflammation on reinfection; and (3) central memory T (TCM) cells, which circulate through the blood and lymphoid organs to produce a second wave of effector T cells on reinfection. TCM cell populations also contain multipotent "memory stem cells," which self-renew to sustain the memory T cell population over time.
Despite this general knowledge, we lack a deep understanding of how different types of memory T cells are generated during an immune response and persist thereafter to provide protective immunity on reinfection. Such knowledge will have a significant impact on the development of vaccines and immunotherapies to fight infectious disease, cancer, and autoimmunity. My lab has spent the past decade elucidating regulatory pathways that control whether an effector T cell lives and adopts a memory cell fate or terminally differentiates into shorter-lived effector cells and dies.
These discoveries have shown that memory T cell fate determination is influenced by environmental cues and a balance of inflammatory and anti-inflammatory cytokines. My lab is trying to understand how signals in the tissue microenvironment and nutrient availability govern changes in gene expression, epigenetic remodeling, and memory T cell metabolism that regulate the types of memory T cells that form and their homeostasis following infection (Figure 1). Work in this area will not only reveal basic principles in the generation and maintenance of memory T cells, but also enhance our understanding of broad biological principles in tissue and tissue stem cell homeostasis, tumor microenvironments, and control of cellular metabolism by environmental conditions. We are focusing on several fundamental questions surrounding the development of protective memory T cells to fight infectious disease and cancer.
First, little is known about how tissues specify memory T cell properties and regulate their long-term survival and homeostasis. To develop a multilayered defense system, TCM, TEM, and TRM cells must distribute themselves broadly and adopt tissue-specific properties dictated by their environments. We do not understand even basic aspects of how this occurs: for example, what are the relevant tissue-trophic factors and cell types that govern this? We are trying to elucidate the key components of the tissue microenvironment that direct transcriptional and epigenetic changes in memory T cells as they undergo environmental adaptation to different tissues and inflammatory conditions. This work is paramount to developing vaccines with tissue-targeting precision that protect against different routes of pathogen entry (e.g., airways, skin, genitals, and blood).
A second major gap exists in our understanding of the metabolic determinants of memory T cell longevity and self-renewal. We know very little about the metabolic and nutrient-utilization pathways that regulate survival and self-renewal of the different memory T cell subsets in various tissues. One recent breakthrough is our discovery that triglyceride storage is essential for the longevity and self-renewal of memory T cells. My lab is studying how lipid synthesis and storage are regulated in memory T cells by T cell growth factors and tissue environments. In addition to its relevance to T cell biology, this work will likely reveal conserved paradigms for metabolic control of stem cell longevity and self-renewal in general.
Third, our understanding of the functional and metabolic connections between T cells and tumors is in its infancy. Central goals of our work are to understand how T cells are regulated by the tumor microenvironment and to determine whether the metabolic rate of the tumor itself modulates that of the infiltrating T cells. We are trying to address the novel concept that nutrient competition between T cells and tumor cells is a key component of immunosuppression in the tumor microenvironment. We will also examine an unexplored process of tumor "metabolic editing," to determine whether T cell immunosurveillance actually selects for cancer cells with higher metabolic rates and intensifies nutrient competition, paradoxically promoting tumor progression.
Grants from the National Institutes of Health, the Burroughs Wellcome Fund, the Cancer Research Institute, the Yale Cancer Center, the Edward Mallinckrodt Jr. Foundation, and the American Asthma Foundation provided support for these projects.
As of December 3, 2014