CD103 fate mapping reveals that intestinal CD103−tissue-resident memory T cells are the primary responders to secondary infection

Tissue-resident memory T (T_RM) cells remain poised in the tissue and mediate robust protection from secondary infection. T_RM cells within the intestine and other tissues are heterogeneous in their phenotype and function; however, the contributions of these T_RM subsets to secondary infection remain poorly defined. To address the plasticity of intestinal T_RM subsets and their role in local and systemic immunity, we generated mice to fate map intestinal CD103⁺ T_RM cells and track their location and function during secondary infection with Yersinia pseudotuberculosis. We found that CD103⁺ T_RM cells remained lodged in the tissue and were poorly reactivated during secondary challenge. CD103^- T_RM cells were the primary responders to secondary infection and expanded within the tissue, with limited contribution from circulating memory T cells. The transcriptional profile of CD103^- T_RM cells demonstrated maintenance of a gene signature similar to circulating T cells along with increased cytokine production and migratory potential. CD103^- T_RM cells also expressed genes associated with T cell receptor (TCR) activation and displayed enhanced TCR-mediated reactivation both in vitro and in vivo compared with their CD103⁺ counterparts. These studies reveal the limited recall potential of CD103⁺ T_RM subsets and the role of CD103^- T_RM cells as central memory-like T cells within peripheral tissues.