Cell-extrinsic CTLA4-mediated regulation of dendritic cell maturation depends on STAT3

Regulatory T (Treg) cells suppress immune responses by downregulating the expression of costimulatory molecules CD80 and CD86 on dendritic cells (DCs) through cytotoxic T lymphocyte antigen 4 (CTLA4). However, it is unclear whether inducible Treg (iTreg) cells can hamper immune responses via the same mechanism. Moreover, whether a reverse signal sent by CTLA4 alone is sufficient to prevent maturation of DCs has never been evaluated. Here, we demonstrate that stimulation of DCs with CTLA4, either expressed by inducible Treg cells or by cross-linking with CTLA4Fc fusion protein, can significantly inhibit LPS-induced CD80 and CD86 mRNA and protein expression in both mouse and human DCs. Importantly, CTLA4Fc-treated DCs had reduced ability to stimulate CD4(+) and CD8(+) T-cell proliferation and cytokine production in both syngeneic and allogeneic settings. We also investigated the molecular mechanism involved in the induction of tolerogenic DCs by CTLA4. We determined that the interaction of CTLA4 with its high affinity ligand CD80 on DCs induces STAT3 phosphorylation followed by reduction of NF-κB activity, leading to suppression of CD80 and CD86 gene transcription and protein production. Our work opens new windows for the generation of tolerogenic DCs that could ultimately be used for treating autoimmune diseases and transplant rejection.