Thymus-derived regulatory T cells restrain pro-inflammatory Th1 responses by downregulating CD70 on dendritic cells

The severity and intensity of autoimmune disease in immune dysregulation, polyendocrinopathy, enteropathy, X‐linked (IPEX) patients and in scurfy mice emphasize the critical role played by thymus‐derived regulatory T cells (tTregs) in maintaining peripheral immune tolerance. However, although tTregs are critical to prevent lethal autoimmunity and excessive inflammatory responses, their suppressive mechanism remains elusive. Here, we demonstrate that tTregs selectively inhibit CD27/CD70‐dependent Th1 priming, while leaving the IL‐12‐dependent pathway unaffected. Immunized mice depleted of tTregs showed an increased response of IFN‐γ‐secreting CD4 + T cells that was strictly reliant on a functional CD27/CD70 pathway. In vitro studies revealed that tTregs downregulate CD70 from the plasma membrane of dendritic cells (DCs) in a CD27‐dependent manner. CD70 downregulation required contact between Tregs and DCs and resulted in endocytosis of CD27 and CD70 into the DC. These findings reveal a novel mechanism by which tTregs can maintain tolerance or prevent excessive, proinflammatory Th1 responses. Synopsis Regulatory T cells (Tregs) control inflammatory responses by inhibiting the CD70‐dependent pathway of Th1 priming while sparing IL‐12 production. By decreasing CD70 cell surface expression on DCs, Tregs enhance the threshold of activation of Th1‐type responses, thereby restraining potentially harmful inflammatory responses. Treg depletion results in enhanced Th1 priming in vivo . Tregs downregulate CD70 protein levels at the plasma membrane of DCs by direct contact in a CD27‐dependent manner. Intercellular transfer of CD27 receptor from T cells to CD70 + DCs leads to co‐internalization of both molecules, thereby limiting CD70 access for conventional T cells. Conventional T cells upregulate CD27 upon activation, suggesting that a similar mechanism may be involved in the termination of immune responses. Graphical Abstract Inhibition of the CD70/CD27 costimulatory pathway for Th1‐helper T‐cell priming exemplifies a new way for Treg‐cell suppression of excessive inflammatory responses.