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

• DOI: 10.1126/sciimmunol.add8454
• Publication Date: 2023-04-21T17:58:06Z
• Authors: Roger Tieu; Qiang Zeng; Daqiang Zhao; Gang Zhang; Neda Feizi; Priyanka Manandhar; Amanda L. Williams; Benjamin Popp; Michelle A. Wood-...; Anthony J. Demetris; J. Yun Tso; Aaron J. Johnson; Lawrence P. Kane; Khodor I. Abou-Daya; Warren D. Shlomchik; Martin H. Oberbar...; Fadi G. Lakkis
• Keywords: Inflammation; Interleukin-15; Memory T Cells; Humans; Antigens; CD8-Positive T-Lymphocytes; 3. Good health

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.