Mesenteric lymph node priming licenses intestinal CD103+CD8 tissue-resident memory T cell development

Abstract CD8 tissue-resident memory T (TRM) cells provide front-line protective immunity at barrier tissues; however, mechanisms regulating their development are not completely understood. Priming dictates the migration of effector CD8 T cells to the tissue, while factors in the tissue induce in situ TRM cell differentiation. Whether priming also regulates in situ differentiation of CD8 TRM cells has not been addressed. Here, we demonstrate that T cell priming in the mesenteric lymph nodes (MLN) was the principal determinant of CD103+ CD8 TRM cell differentiation in the intestine. In contrast, CD8 T cells primed in the spleen were inefficient at differentiating into intestinal CD103+ TRM cells. Moreover, both CD103− and CD103+ naïve T cells were highly efficient in differentiating into CD103+ TRM cells in the intestine after priming in the MLN, suggesting preconditioning of naïve T cells by TGF-b during homeostasis had little impact on intestinal CD103+ TRM cell differentiation. We further demonstrate that MLN priming initiated CD103+ CD8 TRM cell signature gene expression and licensed rapid CD103+ CD8 TRM precursor cell differentiation in response to factors in the tissue by providing retinoic acid signaling to CD8 T cells. Thus, MLN priming is specialized to license intestinal CD103+ CD8 TRM cell development.