Chronic viral infections are a significant cause of morbidity and mortality. CD8 T cell exhaustion is a common occurrence during many chronic infections and this state of dysfunction prevents optimal pathogen control. Reversing o avoiding T cell exhaustion is central to therapeutic and preventative strategies to tret chronic viral infections such as HIV, HCV, HBV and many others. The underlying molecular mechanisms of T cell exhaustion, however, remain poorly understood. We have recently defined progenitor and terminal subsets of exhausted CD8 T cells that are involved in maintaining immunity during chronic viral infections in mice and humans. The overall goal of this proposal is to define the lineage dynamics and transcriptional regulation of these subsets and determine how their control regulates exhaustion and reversibility of function during chronic infections. Several major unanswered questions will be addressed. First, we will define how the severity of chronic infection and the immunoregulatory molecule PD-1 impacts the lineage dynamics, maintenance and fate flexibility of exhausted CD8 T cells subsets. Second, we have identified T-bet and Eomes as the two key transcription factors controlling the progenitor and terminal subsets of exhausted CD8 T cells, but precisely how these transcription factors function is unclear. We will use temporal conditional deletion or overexpression to test when these two transcription factors become critically important to exhausted CD8 T cells and to define when T-bet and Eomes develop context specific function in acute versus chronic infection. Third, we will use conditional deletion and overexpression combined with systems-biology approaches to define the mechanisms of temporally distinct transcriptional coordination by T-bet and Eomes during T cell exhaustion. Thus, the overall hypothesis of this proposal is that the balance between progenitor and terminal subsets of exhausted CD8 T cells controls irreversible commitment to CD8 T cell exhaustion through temporally acquired unique functions of T-bet and Eomes. We will test this hypothesis in the following specific aims:
AIM 1 : To define the signals that regulate progenitor versus terminal populations of exhausted CD8 T cells during chronic viral infection.
AIM 2 : To test whether T-bet and Eomes have temporally distinct functions during acute versus chronic infection.
AIM 3 : To define the transcriptional mechanisms underlying the role of T-bet and Eomes in CD8 T cells exhaustion versus memory.
Chronic infections with viruses such as HIV, HCV and HBV affect half a billion people and are a significant cause of morbidity and mortaliy. T cell dysfunction or 'exhaustion' is a major immunological defect during these infectios and prevents optimal pathogen control and can be modeled with LCMV infection in mice. The studies proposed here will define the cellular and molecular regulation of CD8 T cell exhaustion and provide new insights into how to reverse and avoid T cell exhaustion and improve immunity during these and other chronic infections.
|Bengsch, Bertram; Ohtani, Takuya; Herati, Ramin Sedaghat et al. (2017) Deep immune profiling by mass cytometry links human T and NK cell differentiation and cytotoxic molecule expression patterns. J Immunol Methods :|
|Huang, Alexander C; Postow, Michael A; Orlowski, Robert J et al. (2017) T-cell invigoration to tumour burden ratio associated with anti-PD-1 response. Nature 545:60-65|
|Chen, Zeyu; Stelekati, Erietta; Kurachi, Makoto et al. (2017) miR-150 Regulates Memory CD8 T Cell Differentiation via c-Myb. Cell Rep 20:2584-2597|
|Benci, Joseph L; Xu, Bihui; Qiu, Yu et al. (2016) Tumor Interferon Signaling Regulates a Multigenic Resistance Program to Immune Checkpoint Blockade. Cell 167:1540-1554.e12|
|Barnett, Burton E; Staupe, Ryan P; Odorizzi, Pamela M et al. (2016) Cutting Edge: B Cell-Intrinsic T-bet Expression Is Required To Control Chronic Viral Infection. J Immunol 197:1017-22|
|Attanasio, John; Wherry, E John (2016) Costimulatory and Coinhibitory Receptor Pathways in Infectious Disease. Immunity 44:1052-68|
|Pauken, Kristen E; Sammons, Morgan A; Odorizzi, Pamela M et al. (2016) Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354:1160-1165|
|Bengsch, Bertram; Johnson, Andy L; Kurachi, Makoto et al. (2016) Bioenergetic Insufficiencies Due to Metabolic Alterations Regulated by the Inhibitory Receptor PD-1 Are an Early Driver of CD8(+) T Cell Exhaustion. Immunity 45:358-73|
|Twyman-Saint Victor, Christina; Rech, Andrew J; Maity, Amit et al. (2015) Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 520:373-7|
|Crosby, Erika J; Clark, Megan; Novais, Fernanda O et al. (2015) Lymphocytic Choriomeningitis Virus Expands a Population of NKG2D+CD8+ T Cells That Exacerbates Disease in Mice Coinfected with Leishmania major. J Immunol 195:3301-10|
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