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_RM) localize to barrier tissues and mediate local protection against reinvading pathogens. Circulating central memory (T_CM) and effector memory CD8⁺ T cells (T_EM) also contribute to tissue recall responses, but their potential to form mucosal T_RM remains unclear. Here, we employed adoptive transfer and lymphocytic choriomeningitis virus reinfection models to specifically assess secondary responses of T_CM and T_EM at mucosal sites. Donor T_CM and T_EM 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_CM and T_EM readily gave rise to secondary T_EM. T_CM also formed secondary central memory in lymphoid tissues and T_RM in internal tissues, for example, the liver. Both T_CM and T_EM failed to substantially contribute to resident mucosal memory in the small intestine, while activated intestinal T_RM, but not liver T_RM, efficiently reformed CD103⁺ T_RM. Our findings demonstrate that circulating T_CM and T_EM are limited in generating mucosal T_RM upon reinfection. This may pose important implications on cell therapy and vaccination strategies employing memory CD8⁺ T cells for protection at mucosal sites.