The role of cytotoxic T lymphocyte antigen 4 (CTLA4) in hampering immune responses has been well documented; however, the exact mechanism by which CTLA4 exerts its effect is still under debate. Here, we investigated whether CTLA4 signal alone is sufficient to inhibit dendrtic cell (DC) maturation, stimulatory function, and the molecular mechanisms involved. We demonstrate that stimulation of DCs with CTLA4, either expressed by inducible regulatory T cells (iTregs) or by cross-linking with CTLA4Fc fusion protein, is sufficient to inhibit LPS-induced maturation of both mouse and human DCs. The CTLA4 signaling significantly decreased DC CD80 and CD86 expression as determined by flow cytometry, real-time PCR and Western blot analyses. Importantly, CTLA4Fc-treated DCs had reduced ability to stimulate T cell proliferation and cytokine production in both syngeneic and allogeneic settings. Furthermore, we identified a novel reverse signaling pathway that is dependent on direct activation of STAT3 in DCs and subsequent suppression of NFκB activity. Our data demonstrate, for the first time, that a reverse signal induced by CTLA4 is sufficient to suppress LPS-induced DC maturation and function. This work opens new windows for generation of tolerogenic DCs that could ultimately be used for treating autoimmune diseases and transplant rejection.
- Copyright © 2013 by The American Association of Immunologists, Inc.