UC San Diego

CD4+ T lymphocytes are a key element of adaptive immunity, acting to coordinate and enhance functions of innate cells, B cells, and CD8+ T cells in response to diverse pathogens. Following clearance of the pathogen, a small proportion of effector CD4+ T cells persists and differentiates into long-lived memory cells, which enable a robust secondary response against reinfection and are pivotal in conferring lasting cellular immunity. While the majority of memory cells circulate between tissues and the secondary lymphoid organs (SLOs), tissue-resident memory T cells (TRM) remain lodged in non-lymphoid barrier tissues, particularly at mucosal surfaces like the intestine and serve as sentinels at sites of potential re-exposure to pathogens.

In this dissertation, I aimed to address two overarching questions regarding the biology of virus-specific CD4+ TRM in the small intestine (SI) following acute lymphocytic choriomeningitis virus (LCMV) infection. First, I addressed the developmental origins of CD4+ TRM cells by examining how the resident population is related to circulating CD4+ T helper subsets in SLOs. Second, I investigated potential transcriptional regulators in CD4+ TRM cells, specifically factors with known roles in driving effector versus memory T cell diffentiation. My work revealed that LCMV-specific CD4+ TRM at day 7 of infection shared a gene-expression program and chromatin profile with TH1 cells and progressively acquired a mature TRM program by a memory time point, supporting a developmental relationship between TRM and TH1 subsets. Furthermore, I demonstrated that TRM cells expressed genes associated with both effector and memory T cell fates, including the transcriptional regulators Blimp1, Id2, and Bcl6 which were necessary for CD4+ TRM differentiation. TH1-associated Blimp1 and Id2 were both required for early TRM formation, while TFH-associated Bcl6 initially inhibited TRM differentiation but was critical for development of long-lived TRM cells. These results identified new significance for transcription factors previously associated with circulating CD4+ T cell populations and their roles in driving SI CD4+ TRM differentiation. This work may provide the basis to exploit the protective capacity of this essential memory T cell population and modulate their activity in the immune response.