Secondary infections rejuvenate the intestinal CD103+ tissue-resident memory T cell pool

Resident T lymphocytes (T) protect tissues during pathogen reexposure. Although T phenotype and restricted migratory pattern are established, we have a limited understanding of their response kinetics, stability, and turnover during reinfections. Such characterizations have been restricted by the absence of in vivo fate-mapping systems. We generated two mouse models, one to stably mark CD103 T cells (a marker of T cells) and the other to specifically deplete CD103 T cells. Using these models, we observed that intestinal CD103 T cells became activated during viral or bacterial reinfection, remained organ-confined, and retained their original phenotype but failed to reexpand. Instead, the population was largely rejuvenated by CD103 T cells formed de novo during reinfections. This pattern remained unchanged upon deletion of antigen-specific circulating T cells, indicating that the lack of expansion was not due to competition with circulating subsets. Thus, although intestinal CD103 resident T cells survived long term without antigen, they lacked the ability of classical memory T cells to reexpand. This indicated that CD103 T cell populations could not autonomously maintain themselves. Instead, their numbers were sustained during reinfection via de novo formation from CD103 precursors. Moreover, in contrast to CD103 cells, which require antigen plus inflammation for their activation, CD103 T became fully activated follwing exposure to inflammation alone. Together, our data indicate that primary CD103 resident memory T cells lack secondary expansion potential and require CD103 precursors for their long-term maintenance.