Circulating memory CD8 T cells are limited in forming CD103 tissue-resident memory T cells at mucosal sites after reinfection.

Tissue-resident memory CD8 T cells (T ) localize to barrier tissues and mediate local protection against reinvading pathogens. Circulating central memory (T ) and effector memory CD8 T cells (T ) also contribute to tissue recall responses, but their potential to form mucosal T remains unclear. Here, we employed adoptive transfer and lymphocytic choriomeningitis virus reinfection models to specifically assess secondary responses of T and T at mucosal sites. Donor T and T exhibited robust systemic recall responses, but only limited accumulation in the small intestine, consistent with reduced expression of tissue-homing and -retention molecules. Murine and human circulating memory T cells also exhibited limited CD103 upregulation following TGF-β stimulation. Upon pathogen clearance, T and T readily gave rise to secondary T . T also formed secondary central memory in lymphoid tissues and T in internal tissues, for example, the liver. Both T and T failed to substantially contribute to resident mucosal memory in the small intestine, while activated intestinal T , but not liver T , efficiently reformed CD103 T . Our findings demonstrate that circulating T and T are limited in generating mucosal T upon reinfection. This may pose important implications on cell therapy and vaccination strategies employing memory CD8 T cells for protection at mucosal sites.