TCR transgenic CD8+ T cells activated in the presence of TGF  express FoxP3 and mediate linked suppression of primary immune responses and cardiac allograft rejection

Abstract

Although CD4+CD25+FoxP3+ regulatory T cells play a role in allograft tolerance, the role of CD8+ cells with immunosuppressive function is less clear. To address this issue, spleen cells from Rag-1-deficient TCR transgenic (Tg) mice expressing a receptor for ovalbumin (OVA) in the context of MHC class I (OT1) were activated with OVA expressing antigen-presenting cell (APC) in the presence or absence of exogenous transforming growth factor beta (TGFbeta). TGFbeta inhibited the expression of IFN-gamma, granzyme B and the lytic activity of the OT1 T cells while inducing FoxP3 expression in 5-15% of the cells. By contrast, FoxP3 expression was not detected in naive OT-1 T cells or OT-1 T cells activated without exogenous TGFbeta. TGFbeta-activated OT1 cells inhibited the activation of Kd-specific CD8+ CTL responses by normal B6 T cells and the proliferation by Kd-specific CD4+ TCR Tg T cells, but only if the OVA epitope was co-expressed by Kd+ APC. This antigen-specific inhibitory activity, referred to as linked suppression, was neither mediated by residual lytic activity within the activated OT1 T cells nor did it depend upon IL-10 or TGFbeta. Suppression correlated with inhibition of CD86 expression on CD11c+ APC. TGFbeta-activated OT1 T cells also delayed the rejection of heterotopic, vascularized cardiac allografts mediated by anti-Kd-specific CD4+ TCR Tg T cells, but only if the cardiac allograft expressed both OVA and Kd as transgenes. Prolonged survival of allografts was associated with rapid migration of the FoxP3+ OT1 T cells into the donor heart raising the possibility that suppression may be mediated within the allograft. These data show that TGFbeta-activated CD8+ T cells mediate antigen-specific, APC-focused patterns of suppression in vitro and in vivo.

PPAR-γ agonist rosiglitazone protects peritoneal membrane from dialysis fluid-induced damage

“…Recent studies have found that CD8 þ precursors can be induced to express FoxP3, with acquisition of induced regulatory T cell activity similar to CD4 þ CD25 þ FoxP3 þ cells. 58,59 In this study, we show that the administration of RSG enhances the expression of FoxP3 in the peritoneal cellular influx. The relative proportion of these FoxP3 þ cells that derive from natural or induced regulatory T cells will require further analysis.…”

Antigen, in the Presence of TGF-β, Induces Up-Regulation ofFoxP3gfp+ in CD4+ TCR Transgenic T Cells That Mediate Linked Suppression of CD8+ T Cell Responses

“…These observations that Tregs exhibit functional specificity provide support for the feasibility of using Tregs as immune modulators in the clinic, which would be severely compromised if they were nonspecific in their suppressive function. The capacity of Tregs to suppress effector T cell responses to distinct Ags if both Ags are presented by the same APC, as shown in this study and other reports (47,53,60,61), promises to expand the utility of Tregs for treatment of diseases, such as type 1 diabetes and multiple sclerosis, in which pathogenic T cells with specificities for multiple Ags are involved, without the need to identify each epitope.…”

“…After 4 -5 days, the cultures were harvested and assayed for lytic activity using the H-2 b tumor cell line (EL4, an MHC class II-negative T cell lymphoma) (44), E.G7-OVA (EL4 cell line that expresses the chicken OVA gene (44), and the H-2 d cell line (P815) as targets for the CTL assays. CTL activity was measured using a modification of published flow cytometry methods using CFSE-labeled targets (45,46) to directly count the number of viable target cells, as previously described (47). The ratio of viable Ag ϩ /Ag Ϫ cells in each experimental tube divided by the same ratio in the control tubes gives a measure of Agspecific cytotoxicity by the formula: percentage of specific cytotoxicity ϭ 100…”

The role of T helper 17 (Th17) and regulatory T cells (Treg) in human organ transplantation and autoimmune disease

“…+ CD28 -cells [129][130][131][132], CD3 + CD4 -CD8 -cells [133,134] and naturally occurring CD4 + CD25 + T cells [135]. Given that both human and murine knock-outs for CD4…”