Sunday, May 11, 2025
5/11/2025
Tissue-specific adaptions to promote localized T cell memory - SUMMARY CD8 T cells are a critical component of the immune response to intracellular infections and malignancies given their ability to directly kill target cells in tissues. After the resolution of an acute infection, a small proportion of antigen-specific T cells persists as long-lived memory cells and provides protection upon re-infection. Memory CD8 T cell populations show a spectrum of phenotypic, functional, and recirculation capacities as well as the potential for secondary memory formation. Memory T cells have traditionally been studied in blood and secondary lymphoid organs, with central memory cells found recirculating between the blood and lymphoid tissues and effector memory T cells found in blood and tissues. It is now understood that long-lived, tissue- resident memory CD8 T cells (TRM) comprise a significant portion of the memory immune response, mediating host protection at sites of potential reinfection and, in some cases, causing immunopathology associated with chronic infection and autoimmunity. We find that the transition of immune cells from a itinerant, recirculating pattern to established residence in a specific tissue is accompanied by significant changes in gene expression and genome accessibility. These T cell adaptations to the unique tissue environment mediate formation, survival, and function of TRM populations. The transcriptional repressor Hic1 has recently been identified as a critical regulator of the small intestine (SI) TRM population generated in response to acute viral infection. These findings raise many new questions, such as (1) Which cues and cellular interactions regulate these adaptations? (2) How are transcriptional circuits controlling tissue residency, immune function, and memory potential integrated? And (3) What are the specific targets of Hic1 and its mechanisms of action? In this proposal, we will address the underlying mechanisms of Hic1 activity in establishing TRM, its role in the transcriptional network governing SI residency, and its importance in TRM secondary memory potential. We propose the following: Aim 1: Define the role of Hic1 in the regulation of TRM differentiation and maintenance and the signals that induce Hic1 expression in infection; Aim 2: Elucidate the role of Hic1 in the transcriptional network governing CD8 T residency in the small intestine, and Aim 3: Determine the tissue-specific regulation of TRM fates and the potential for proliferation and contribution to memory responses. These studies will inform efforts to induce “tissue-tailored” immune responses to improve vaccine efficacy.
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