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 in order to develop new methods of immunotherapy that enhance anti-tumor responses. Using several powerful model systems of infection or cancer in mice, we are elucidating 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.
Extensive Research Description
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 re-infection. Several types of memory T cells, which differ by their phenotypes, functions and anatomical locations, are produced to create a sophisticated, multi-layered 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 upon 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 upon reinfection. TCM cell populations also contain multipotent “memory stem cells" that 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 upon 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 last decade elucidating regulatory pathways that control whether an effector T cell lives and adopts memory cell fates 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. Currently, my lab is trying to understand how signals in the tissue microenvironment and nutrient availability governs 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 will 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. Currently, 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. We are studying how lipid synthesis and storage are regulated in memory T cells by T cell growth factors and tissue environments. In addition to the 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 determine if the metabolic rate of the tumor itself modulates that of the infiltrating T cells. We are also addressing the novel concept that nutrient competition between the 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 if T cell immunosurveillance actually selects for cancer cells with higher metabolic rates and intensifies nutrient competition, paradoxically promoting tumor progression.
Memory CD8 T cell differentiation
Memory CD4 T cell differentiation
Chronic viral infection
Tumor Immunology and Immunotherapy
- Staron M, Gray S, Li MO, Ip WK, Kaech SM. FoxO1 directly regulates the expression of PD-1 and sustains viral specific CD8+ T-cell responses during chronic infection. Immunity 41(5) 802-14 (2014). PMCID in Progress
- Laidlaw BJ, Zhang N, Craft J, Kaech SM. CD4 T cells required for development and function of tissue resident memory CD8 T cells through a T-bet-dependent mechanism. Immunity 41(4):633-45 (2014). PMCID in Progress.
- Ho PC, Meeth KM, Tsui YC, Srivastava B, Bosenberg MW, Kaech SM. Immune-based antitumor effects of BRAF Inhibitors rely on signaling by CD40L and IFN-?. Cancer Res, 74(12):3205-17 (2014). PMCID: PMC4063281.
- Cui W, Joshi NS, Liu Y, Meng H, Kleinstein SH and Kaech SM. TLR4 ligands LPS and MPLA differentially regulate effector and memory CD8+ T cell differentiation. J Immunol, 92(9):4221-32 (2014). PMCID: PMC4071140.
- Ray JP, Marshall HD, Laidlaw BJ, Staron MM, Kaech SM, Craft J. Transcription Factor STAT3 and Type I Interferons Are Corepressive Insulators for Differentiation of Follicular Helper and T Helper 1 Cells. Immunity 40(3):367-77 (2014). PMCID: PMC3992517.
- Parish, IA, Marshall HD, Staron M, Lang PA, Brüstle A, Chen JH, Cui W, Ohashi PS, Weaver CT and Kaech SM. Blimp-1 triggers the formation of immunoregulatory IL-10 producing Th1 cells during chronic viral infection. J Clin Invest, 124(8):3455-68 (2014). PM
- Demento SL, Cui W, Criscione JM, Stern E, Tulipan J, Kaech SM, Fahmy TM. Role of sustained antigen release from nanoparticle vaccines in shaping the T cell memory phenotype. Biomaterials. 19:4957-64 (2012). PMID:224840449. PMCID in Progress.
- Cui W, Liu Y, Weinstein JS, Craft J & Kaech SM. An IL-21/IL-10/STAT3 pathway is critical for functional maturation of memory CD8+ T cells. Immunity 35:792-805 (2011). PMCID in progress.
- Marshall HD, Chandele A, Jung YW, Meng H, Poholek AC, Parish IA, Rustishauser R, Cui W, Kleinstein SH, Craft J and Kaech SM. Differential Expression of Ly6C and T-bet Distinguish Effector and Memory Th1 CD4(+) Cell Properties during Viral Infection. Immun
- Joshi NS, Cui W, Dominguez CX, Chen JH, Hand TW and Kaech SM. Increased numbers of pre-existing memory CD8 T cells and decreased T-bet expression can restrain terminal differentiation of secondary effector and memory CD8 T cells. J Immunol 187(8):4068-76
- Jung YW, Rutishauser R, Nikhil JS, Haberman AM and Kaech SM. Differential localization of effector and memory CD8 T cell subsets in lymphoid organs during acute viral infection. J Immunol 185:5315-25 (2010). PMCID in progress.
- Hand TW, Jung YW, Cui W, Sefik E, Liu Y, Joshi NS, Chandele A and Kaech SM. Differential effects of STAT5 and P13K/AKT signaling on effector and memory CD8 T cell survival. PNAS 107:16601-6 (2010). PMCID: PMC2944719.
- Poholek AC, Hansen K, Hernandez SG, Eto D, Chandele A, Dong, X, Odegard JM, Kaech SM, Dent AL, Crotty S and Craft J. Bcl6 regulation and TFH cell development. J Immunol 185:313-26 (2010). PMCID: PMC2891136.
- Rutishauser RL, Martins GA, Kalachikov S, Chandele A, Parish IA, Jacob J, Calame K, Kaech SM. Blimp-1 is Required for the Terminal Differentiation of Virus-Specific Effector and Memory CD8 T cells. Immunity 31: 296-308 (2009).
- Cui W, Joshi NS, Jiang A, Whitmire JK, Whitton JL, Kaech SM. Effects of Signal 3 during CD8 T cell priming: Bystander Production of IL-12 enhances effector T cell expansion but promotes terminal differentiation. Vaccine 27: 2177-87 (2009). PMID: 1920138
- Chandele A, Joshi NS, Zhu J, Paul WE, Leonard WJ, Kaech SM. Formation of IL-7Rahi and IL-7Ralo CD8 T Cells during Infection is Regulated by the Opposing Functions of GABPa and Gfi-1. J Immunol 8: 5309-19 (2008). PMID: 18390712.
- Joshi NS, Cui W, Chandele A, Heung K-L, Urso D, Hagman J, Gapin L, Kaech SM. Inflammation Directs Memory Precursor and Short-Lived Effector CD8+ T Cell Fates via the Graded Expression of T-Bet Transcription Factor. Immunity 27: 281-295 (2007). PMID: 1772
- Kaech SM and Wherry EJ. Heterogeneity and Cell Fate Decisions in Effector and Memory CD8+ T Cell Differentiation During Viral Infection. Immunity 27:393-405 (2007). PMID: 17892848.
- Hand T, Morre M, Kaech SM. Expression of Interleukin-7 Receptor a Is Necessary but not Sufficient for the Formation of Memory CD8 T Cells During Viral Infection. PNAS 104: 11730-11735 (2007). PMID: 17609371.
- Kaech, S.M., Tan, J.T., Wherry, E.J., Konieczny, B.T., Surh, C.D., and Ahmed, R. (2003). Selective expression of the IL-7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nature Immunol. 4:1191-98.
- Production of IL-10 by CD4(+) regulatory T cells during the resolution of infection promotes the maturation of memory CD8(+) T cells. Laidlaw BJ, Cui W, Amezquita RA, Gray SM, Guan T, Lu Y, Kobayashi Y, Flavell RA, Kleinstein SH, Craft J, Kaech SM. Nat Immunol. 2015 Aug;16(8):871-9.