The role of TCF1 in CD8+ tissue resident memory T cell formation and maintenance across distinct tissues

University Of California, San Diego, La Jolla CA

Investigators

Abstract

SUMMARY Formation of long-lived memory T cells is a critical feature of the adaptive immune system which enables the efficient control of recurrent infection. Tissue-resident memory T (TRM) cells are a unique and transcriptionally heterogenous population of memory T cells that provide host protection against pathogens through their positioning within barrier tissues and rapid effector response. Current treatments for viral infections lack the ability to enhance the TRM cell protective response largely because our understanding of TRM biology lags that of circulating memory T cell populations. To dissect the transcriptional regulators of TRM across distinct tissues, I have chosen to focus on T cell factor 1 (TCF1), a transcription factor that is critical for the formation of central memory T cells yet is largely unstudied in the context of TRM cell biology. TCF1 has been shown to repress lung TRM, however its role in TRM cell formation and maintenance in other non-lymphoid tissues such as the intestines, salivary gland, kidney, liver, and pancreas are unknown. Furthermore, TCF1 is expressed in multiple isoforms yet the role of the individual isoforms of TCF1 have never been investigated in the context of TRM cell formation in any tissue. Additionally, there is a growing body of evidence which suggests that TCF1 expression during the first week of an acute viral infection defines cells that are fated to become memory cells versus terminal effector cells. However, the mechanism behind TCF1 regulation of this fate decision remains largely unknown. This proposal seeks to address these gaps in knowledge by investigating the hypothesis that TCF1 has distinct roles in regulating CD8+ T cells throughout the course of infection from effector CD8+ cell expansion, memory precursor formation, and TRM cell formation and maintenance. To investigate this hypothesis, we will complete the following two specific aims: (Aim 1) Determine the role of TCF1 in the formation and maintenance of CD8+ TRM cells across distinct tissues; (Aim 2) Investigate the role of TCF1 in early effector CD8+ expansion and memory precursor cell formation across distinct tissues. Identification of the molecular mechanisms regulating TRM cell formation and maintenance will build on our understanding of the transcriptional regulation of TRM and will have a positive impact on therapeutics designed to modulate tissue-specific TRM. The experiments and career development opportunities outlines in this proposal will greatly prepare the applicant for a successful career in academic research.