Local Induction of Immunosuppressive CD8+ T Cells in the Gut-Associated Lymphoid Tissues

Background: In contrast to intestinal CD4(+) regulatory T cells (T-regs), the generation and function of immunomodulatory intestinal CD8(+) T cells is less well defined. To dissect the immunologic mechanisms of CD8(+) T cell function in the mucosa, reactivity against hemagglutinin (HA) expressed in intestinal epithelial cells of mice bearing a MHC class-I-restricted T-cell-receptor specific for HA was studied. Methodology and Principal Findings: HA-specific CD8(+) T cells were isolated from gut-associated tissues and phenotypically and functionally characterized for the expression of Foxp3(+) and their suppressive capacity. We demonstrate that intestinal HA expression led to peripheral induction of HA-specific CD8(+) Foxp3(+) T cells. Antigen-experienced CD8(+) T cells in this transgenic mouse model suppressed the proliferation of CD8(+) and CD4(+) T cells in vitro. Gene expression analysis of suppressive HA-specific CD8(+) T cells revealed a specific up-regulation of CD103, Nrp1, Tnfrsf9 and Pdcd1, molecules also expressed on CD4(+) T-reg subsets. Finally, gut-associated dendritic cells were able to induce HA-specific CD8+ Foxp3(+) T cells. Conclusion and Significance: We demonstrate that gut specific antigen presentation is sufficient to induce CD8(+) T-regs in vivo which may maintain intestinal homeostasis by down-modulating effector functions of T cells.