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

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.

CD8+Foxp3+ T cells share developmental and phenotypic features with classical CD4+Foxp3+ regulatory T cells but lack potent suppressive activity

“…Furthermore, adoptive transfer of induced CD8 1 Foxp3 1 T cells did not ameliorate disease in an OVA-based allergic airway inflammation model (data not shown). Previous studies have reported the suppressive capacity of TGF-b-induced CD8 1 T cells [17,31,34,38], which in principle does not contradict our data. First, several studies did not compare the strength of suppression to that of CD4 1 Tregs [31,34,38], which depend on Foxp3 [3].…”

“…Previous studies have reported the suppressive capacity of TGF-b-induced CD8 1 T cells [17,31,34,38], which in principle does not contradict our data. First, several studies did not compare the strength of suppression to that of CD4 1 Tregs [31,34,38], which depend on Foxp3 [3]. Second, suppressive CD8 1 T cells were isolated either based on CD25 expression [17] (also broadly up-regulated on activated Foxp3 À T cells, at least in the absence of IL-6), or were tested without further separation for suppressive function [31,38], thereby not allowing for discrimination between Foxp3 1 and Foxp3 À subsets.…”

“…Notably, the Foxp3 induction efficiency in this setting was about five times lower, probably due to the inhibitory effects of DC. Foxp3 induction was similarly suboptimal when a different TCR transgenic system and mLN-DC or polyclonal stimulation in the presence of BM-derived DC were used [17,34]. Considering that MHC-class-I is broadly expressed, it is possible that CD8 1 Foxp3 1 T cells might preferentially develop in response to endogenous or foreign intracellular antigens presented by cell types incapable of co-stimulation, in specific compartments where TGF-b and RA are available.…”

“…Considering that MHC-class-I is broadly expressed, it is possible that CD8 1 Foxp3 1 T cells might preferentially develop in response to endogenous or foreign intracellular antigens presented by cell types incapable of co-stimulation, in specific compartments where TGF-b and RA are available. Indeed, ectopic antigen expression controlled by the villin promoter has recently been shown to result in expansion of intestinal CD8 1 Foxp3 1 T cells when crossed to TCR transgenic mice specific for the same antigen [34]. Additionally, CD8 1 Foxp3 1 T cells have been shown to expand during simian immunodeficiency virus infection at sites of viral replication [35] and accumulate in colorectal cancer tissue [36], which may be a result of direct antigen presentation by infected or transformed cells, respectively.…”

In vitroinduced CD8+regulatory T cells inhibit skin inflammation

“…Here, the most prominent population is CD8 + CD28 -and suppressive via IL-10 secretion [8]. Furthermore, the induction of CD8 + regulatory T cells through the stimulation of the T-cell receptor mostly leads to the expression of Foxp3 in these T cells [3,4,[9][10][11]. Most of the adaptive CD8 + regulatory T cells appear to suppress via a cell-contact-dependent mechanism.…”