Antigen-specific induced Foxp3⁺regulatory T cells are generated following CD40/CD154 blockade

Abstract

Blockade of the CD40/CD154 pathway potently attenuates T-cell responses in models of autoimmunity, inflammation, and transplantation. Indeed, CD40 pathway blockade remains one of the most powerful methods of prolonging graft survival in models of transplantation. But despite this effectiveness, the cellular and molecular mechanisms underlying the protective effects of CD40 pathway blockade are incompletely understood. Furthermore, the relative contributions of deletion, anergy, and regulation have not been measured in a model in which donor-reactive CD4 + and CD8 + T-cell responses can be assessed simultaneously. To investigate the impact of CD40/CD154 pathway blockade on graft-specific T-cell responses, a transgenic mouse model was used in which recipients containing ovalbumin-specific CD4 + and CD8 + TCR transgenic T cells were grafted with skin expressing ovalbumin in the presence or absence of anti-CD154 and donor-specific transfusion. The results indicated that CD154 blockade altered the kinetics of donorreactive CD8 + T-cell expansion, delaying differentiation into IFN-γ + TNF + multifunctional cytokine producers. The eventual differentiation of cytokine-producing effectors in tolerant animals coincided with the emergence of an antigen-specific CD4 + CD25 hi Foxp3 + T-cell population, which did not arise from endogenous natural T reg but rather were peripherally generated from naïve Foxp3 − precursors.costimulation blockade B lockade of the CD40/CD154 pathway has long been appreciated as a potent means of inhibiting alloreactive T-cell responses and prolonging graft survival. But despite this pronounced effect on allograft survival in both murine and nonhuman primate models (1-3), clinical trials using anti-CD154 mAbs in transplantation were halted due to thromboembolic complications, likely related to the expression of CD154 on platelets (4, 5). However, recent studies using anti-CD40 mAbs in both murine and nonhuman primate models demonstrated comparable efficacy to CD154 blockade, and thus significant interest in the pathway remains (6-9).Early studies by Parker et al. (3) described the treatment combination of anti-CD154 and donor-specific transfusion (DST) for the induction of immune tolerance in transplantation. Several groups have since demonstrated the potent effects of this combined therapy in the prolongation of islet (3, 10, 11), cardiac (12), skin (10, 13), and kidney (14, 15) allograft survival in murine and nonhuman primate models. Although costimulation blockade has been associated with T-cell anergy (16) or deletion (17, 18), elucidation of the precise independent and synergistic effects of DST and anti-CD154 on the kinetics of donor-reactive CD4 + and CD8 + effector T-cell expansion has been limited because of the inability to identify and track graft-specific T cells in fully allogeneic models.Importantly, studies by Taylor et al. (19) demonstrated that CD4 + CD25 + regulatory T cells (T reg ) are required for tolerance induced via CD40/CD154 pathway blockade in a graft-versushost model....

Adjuvants That Improve the Ratio of Antigen-Specific Effector to Regulatory T Cells Enhance Tumor Immunity

“…Data are emerging on the Teff and antigen-specific Treg relationships in autoimmunity and transplantation. Immunotherapies that enhance antigenspecific Treg expansion and suppressive function delayed multi-cytokine-producing Teff activation, resulting in disease control (41,42). To date, the relationship between antigenspecific Teffs and Tregs has not been examined in detail in cancer, although some in vitro and observational reports exist [19][20][21].…”

CD45 ligation expands Tregs by promoting interactions with DCs

“…Alternatively, tolerance may be enhanced by expanding Tregs in vivo. iTregs can be induced under specialized circumstances (2,5,(7)(8)(9)(10)(11). While this can contribute to systemic tolerance, induction of iTregs during an active immune response has been observed primarily in TCR transgenic models.…”

A Novel Approach Inducing Transplant Tolerance By Activated Invariant Natural Killer T Cells With Co-Stimulatory Blockade.

“…The ratio of Tregs to antigen-specific Teffs has been previously identified as a predictor of the potential protective effects of Tregs (28,56). From those data, it is speculated that alloreactivity could be regulated, and allo-hematopoietic cell engraftment would be facilitated when the number and activity of Tregs overcome those of Teffs.…”

“…Anti-CD40L in this study seems to be a switch that could control immune-direction of The importance of Tregs for peripheral tolerance induction has been proved (26,28).…”