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

Abstract

CD4+CD25+ regulatory T cells (Tregs) inhibit immune responses to a variety of Ags, but their specificity and mechanism of suppression are controversial. This controversy is largely because many studies focused on natural Tregs with undefined specificities and suppression has frequently been measured on polyclonal T cell responses. To address the issue of specificity further, we have bred Kd-specific, CD4+ TCR (TCR75) transgenic mice to Foxp3gfp knockin reporter mice to permit sorting of Tregs with a known specificity. Foxp3gfp.TCR75 mice did not express significant numbers of natural FoxP3+ Tregs expressing the TCR75 transgenes, but FoxP3 expression was induced by stimulating with Kd plus TGF-β. The resulting GFP+ TCR75 cells were anergic, whereas the GFP− TCR75 cells proliferated upon restimulation with Kd peptide. Yet both exhibited severely reduced expression of intracellular IFN-γ and TNF-α upon restimulation. GFP+, but not GFP−, TCR75 T cells suppressed responses by naive TCR75 T cells and by nontransgenic spleen cells stimulated with anti-CD3. GFP+ TCR75 cells also inhibited polyclonal C57BL/6 anti-Kd CTL responses if the APC expressed Kd and both MHC class I and class II, and responses by OT1 T cells to B6.Kd.OVA but not B6.Kd plus OVA expressing APC, demonstrating linked-suppression of CD8 responses. Thus, Tregs exhibit a greater degree of specificity in vitro than previously appreciated. The observation that Tregs and responder T cells must recognize the same APC provides a mechanistic explanation for the observation that Tregs must be in direct contact with effector T cells to suppress their responses.

CD8+ suppressor T cells resurrected

“…Breeding TCR Tg mice with the Foxp3 gfp reporter mice allowed us to demonstrate that CD4 ϩ Foxp3 ϩ TCR Tg T cells could be induced by activation with antigen in the presence of TGF-␤ and IL-2 [36]. These studies also verified that the suppressive activity was a function of the GFP ϩ but not the GFP Ϫ transforming growth factor (TGF)-␤-activated T cells.…”

Preferential Costimulation by CD80 Results in IL-10-Dependent TGF-β1+-Adaptive Regulatory T Cell Generation

“…Although Ag presentation in the presence of IL-10 or by IL-10-exposed DCs is known to induce TGF-␤1-producing T cells, TGF-␤1 is known to induce Foxp3 ϩ and IL-10 ϩ Tregs (23,24). What is responsible for the induction of TGF-␤1 ϩ T cell upon of Ag presentation in the presence of dominant costimulation by CD80?…”

Targeting MHC Class I Monomers to Dendritic Cells Inhibits the Indirect Pathway of Allorecognition and the Production of IgG Alloantibodies Leading to Long-Term Allograft Survival

“…By using this approach, we were able to induce indefinite graft survival in the majority of animals who were treated with the 33D1-K d monomer conjugate in combination with anti-CD8 (Fig. 5A) Because these animals lack b 2 -microglobulin, their cells are not able to express MHC class I molecules on their surface and cannot stimulate CD8 + T cells, whereas their DCs are still able to indirectly present the K d peptide and stimulate TCR75 T cells (23). As shown in Fig.…”