Cytokine-driven integrin expression controls CD8 T cell homeostasis

Abstract

Abstract The peripheral CD8 T cell pool comprises a mixture of naïve and memory-phenotype (MP) cells. While naïve CD8 T cells are continuously produced and supplied through thymic export, MP CD8 T cells are mostly generated by antigen activation or cytokine-mediated differentiation and maintained by homeostatic cytokines, such as IL-15. Both naïve and MP CD8 T cells are necessary to mount vigorous immune responses against new and reoccurring pathogens. But, the mechanisms through which MP CD8 T cells would avoid competing with naïve CD8 T cells for limited space and survival cues remain largely unsolved. Here, we report that integrin CD103 plays a critical role in this process. CD103 is highly expressed on naïve CD8 T cells to mediate adhesion to cells and tissues that are abundant for its ligand, E-cadherin. Interestingly, homeostatic cytokine signaling that drives MP CD8 T cell differentiation potently downregulated the expression of CD103, dissociating them from potential competition with CD103-positive naïve CD8 T cells. Conversely, the forced expression of CD103 on MP CD8 T cells resulted in the accumulation of MP CD8 T cells and selective loss of naïve CD8 T cells. Mechanistically, we identified a subset of dendritic cells that expresses E-cadherin (E-cad +DCs), that would interact with CD103-positive CD8 T cells to provide survival signals and control their maintenance. Collectively, our results suggest that IL-15-mediated downregulation of CD103 contributes to balancing the size and composition of the peripheral CD8 T cell pool, revealing a previously unappreciated role of cytokine-driven integrin expression in controlling CD8 T cell homeostasis. This work was supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research.