UC San Diego

The adaptive immune system mounts a specialized response against invading pathogens and provides long lasting protection against secondary infection. During infections, antigen specific CD4 T cells differentiate into distinct effector T helper subsets, in which a portion persists after pathogen clearance and contributes to the generation of tissue-resident memory T cells (Trm) in non-lymphoid tissues (NLTs). In context of acute viral infections such as Lymphocytic choriomeningitis (LCMV-Armstrong), it is unknown which of the circulating helper T cell subsets, give rise to Trm populations during the effector phase. In LCMV infection, both T follicular helper (Tfh) or T helper type 1 (Th1) effector T cell subsets are generated and give rise to long-lived memory T cell subsets in circulation, with Tfh memory T cells representing the majority of cells at memory time points. We studied these subsets in the secondary lymphoid organs (SLOs) and the intraepithelial layer (IEL) of the small intestine (SI) throughout LCMV infection to investigate whether Trm shared characteristics with effector populations and to understand the developmental relationship between circulating CD4 memory T cells and CD4 Trm. Circulating effector Th1 cells and Trm populations in the IEL displayed comparable surface protein and transcription factor expression. Trm populations solely expressed Th1 lineage marker, SLAM, and a substantial portion retained expression of the Th1-driving transcription factor, Blimp1. However, CD4 cells in the IEL expressed tissue retention marker CD69 significantly more than circulating Th1, confirming their Trm profile. These findings distinguish the Trm population in the IEL from circulating Th1 effector and memory populations and suggest Th1 effector cells are a Trm precursor. This study sheds light on CD4 Trm development and unveils subset programming that may serve as potential targets for improving vaccines that elicit CD4 Trm responses.