Tissue-resident memory T cell maintenance during antigen persistence requires both cognate antigen and interleukin-15
Roger Tieu, Qiang Zeng, Daqiang Zhao, Gang Zhang, Neda Feizi, Priyanka Manandhar, Amanda Williams, Benjamin Popp, Michelle A. Wood, Anthony J. Demetris, J. Yun Tso, Aaron J. Johnson, Larry Kane, Khodor I. Abou‐Daya, Warren D. Shlomchik, Martin H. Oberbarnscheidt, Fadi G. Lakkis
Abstract
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.