Tissue-resident memory T cell maintenance during antigen persistence requires both cognate antigen and interleukin-15

Our understanding of tissue-resident memory T (T_RM) cell biology has been largely developed from acute infection models in which antigen is cleared and sterilizing immunity is achieved. Less is known about T_RM cells in the context of chronic antigen persistence and inflammation. We investigated factors that underlie T_RM maintenance in a kidney transplantation model in which T_RM cells drive rejection. In contrast to acute infection, we found that T_RM cells declined markedly in the absence of cognate antigen, antigen presentation, or antigen sensing by the T cells. Depletion of graft-infiltrating dendritic cells or interruption of antigen presentation after T_RM cells were established was sufficient to disrupt T_RM maintenance and reduce allograft pathology. Likewise, removal of IL-15 transpresentation or of the IL-15 receptor on T cells during T_RM maintenance led to a decline in T_RM cells, and IL-15 receptor blockade prevented chronic rejection. Therefore, antigen and IL-15 presented by dendritic cells play nonredundant key roles in CD8 T_RM cell maintenance in settings of antigen persistence and inflammation. These findings provide insights that could lead to improved treatment of chronic transplant rejection and autoimmunity.