Memory CD8 T cells play a critical role in mediating long-term immunity against infectious disease. Developing long-lived memory CD8 T cells is currently the paramount goal of many vaccines that will fight chronic infections, such as HIV, malaria and Hepatitis C, and also against certain types of cancers. Memory CD8 T cells provide long-lived immunological protection because they proliferate, secrete antiviral cytokines and kill infected cells more rapidly than nave T cells upon antigen encounter. Memory CD8 T cells can persist for great lengths of time (up to one's lifetime) and a number of stem cell-like properties are bestowed onto these cells, such as telomerase expression and the ability to self-renew through homeostatic turnover. These functional attributes, along with the sheer increase in precursor frequency of pathogen-specific T cells, constitute the basis of long-term memory T cell-mediated immunity. Understanding how long-lived memory T cells that protect against secondary infections are formed and maintained is an important area of research because of their profound role in human health. We have identified a novel pathway controlling the formation of mature antiviral memory CD8 T cells and their precursors that involves the actions of IL-10, IL-21 and STAT3. Based on our findings, we hypothesize that memory cell fates are not necessarily programmed in activated CD8 T cells, but rather, require signaling from IL-10 and IL-21 to sustain mature memory CD8 T cell differentiation states and central memory (TCM) properties. In the absence of these signals, we postulate that antigen-specific CD8 T cells are prone to spontaneous effector cell differentiation and IL-10/IL-21/SOCS3 act to buffer memory CD8 T cells from steady-state or bystander inflammatory bursts to sustain memory cell potential and protective responses. In this grant we will use state of the art techniques to determine (1) when during infection IL-10/IL-21/STAT3 signaling influences memory cell fates, (2) if T cells are the physiologically relevant producers or IL-10 and IL-21 for memory CD8 T cell development, (3) whether blocking IL-2 or IL-12 signaling rescues memory CD8 T cell development in the absence of STAT3, and (4) how STAT3 and STAT4/STAT5 reciprocally control 'effector' and 'memory' CD8 T cell gene expression. This work is of high impact because it provides new mechanistic insight into cytokines and transcription factors that regulate memory CD8 T cell differentiation and homeostasis, and this could lead to improved therapeutic modulation of T cell differentiation and function during vaccination, cancer treatments and other types of immune-based therapies.
Memory CD8 T cells persist for long periods after primary infection, yet little is known about the factors that sustain these cells and their protective qualities. This grant will identify important mechanisms of IL-10/IL-21/STAT3 signaling in memory CD8 T cell differentiation, which can be applied to improve vaccines and other immunotherapies.
|Guan, Tianxia; Dominguez, Claudia X; Amezquita, Robert A et al. (2018) ZEB1, ZEB2, and the miR-200 family form a counterregulatory network to regulate CD8+ T cell fates. J Exp Med 215:1153-1168|
|Herndler-Brandstetter, Dietmar; Ishigame, Harumichi; Shinnakasu, Ryo et al. (2018) KLRG1+ Effector CD8+ T Cells Lose KLRG1, Differentiate into All Memory T Cell Lineages, and Convey Enhanced Protective Immunity. Immunity 48:716-729.e8|
|Gray, Simon M; Amezquita, Robert A; Guan, Tianxia et al. (2017) Polycomb Repressive Complex 2-Mediated Chromatin Repression Guides Effector CD8+ T Cell Terminal Differentiation and Loss of Multipotency. Immunity 46:596-608|
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|Cui, Guoliang; Staron, Matthew M; Gray, Simon M et al. (2015) IL-7-Induced Glycerol Transport and TAG Synthesis Promotes Memory CD8+ T Cell Longevity. Cell 161:750-61|
|Dominguez, Claudia X; Amezquita, Robert A; Guan, Tianxia et al. (2015) The transcription factors ZEB2 and T-bet cooperate to program cytotoxic T cell terminal differentiation in response to LCMV viral infection. J Exp Med 212:2041-56|
|Laidlaw, Brian J; Cui, Weiguo; Amezquita, Robert A et al. (2015) Production of IL-10 by CD4(+) regulatory T cells during the resolution of infection promotes the maturation of memory CD8(+) T cells. Nat Immunol 16:871-9|
|Ho, Ping-Chih; Bihuniak, Jessica Dauz; Macintyre, Andrew N et al. (2015) Phosphoenolpyruvate Is a Metabolic Checkpoint of Anti-tumor T Cell Responses. Cell 162:1217-28|
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