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

Diana Fleissner,Wiebke Hansen,Robert Geffers,Jan Buer,Astrid M Westendorf,Derya Unutmaz

doi:10.1371/journal.pone.0015373

Diana Fleissner, Wiebke Hansen + Show 4 more

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https://doi.org/10.1371/journal.pone.0015373

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Abstract

BackgroundIn contrast to intestinal CD4+ regulatory T cells (Tregs), 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 FindingsHA-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+ Treg subsets. Finally, gut-associated dendritic cells were able to induce HA-specific CD8+Foxp3+ T cells.Conclusion and SignificanceWe demonstrate that gut specific antigen presentation is sufficient to induce CD8+ Tregs in vivo which may maintain intestinal homeostasis by down-modulating effector functions of T cells.

Highlights

Tolerance to self antigens is crucial to maintain intestinal homeostasis and to avoid autoimmunity in the gut
We demonstrate that gut specific antigen presentation is sufficient to induce CD8+ Tregs in vivo which may maintain intestinal homeostasis by down-modulating effector functions of T cells
Menager-Marcq et al have demonstrated that CD8+CD282 but not CD8+CD28+ T cells freshly isolated from the spleen or the gut efficiently prevented the development of colitis in an adoptive transfer model where the injection of CD45RBhigh into RAG2-deficient mice led to intestinal inflammation [8]

Summary

Introduction

Tolerance to self antigens is crucial to maintain intestinal homeostasis and to avoid autoimmunity in the gut. A role for CD8+ T cells in the in vivo suppression of self-reactive T cells has been described [1]. A number of CD8+ T cell clones with inhibitory activity have been reported [2,3,4,5], the nature of primary CD8+ Tregs and the mechanisms underlying their generation remain elusive. In contrast to intestinal CD4+ regulatory T cells (Tregs), 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-cellreceptor specific for HA was studied

Methods

Results

Conclusion