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Publication : CTLA4Ig inhibits effector T cells through regulatory T cells and TGF-β.

First Author  Deppong CM Year  2013
Journal  J Immunol Volume  191
Issue  6 Pages  3082-9
PubMed ID  23956428 Mgi Jnum  J:205876
Mgi Id  MGI:5546561 Doi  10.4049/jimmunol.1300830
Citation  Deppong CM, et al. (2013) CTLA4Ig inhibits effector T cells through regulatory T cells and TGF-beta. J Immunol 191(6):3082-9
abstractText  The CD28 costimulatory receptor is a critical regulator of T cell function, making it an attractive therapeutic target for the treatment of immune-mediated diseases. CTLA4Ig, now approved for use in humans, prevents naive T cell activation by binding to B7 proteins and blocking engagement of CD28. However, CTLA4Ig suppresses inflammation even if administered when disease is established, suggesting alternative mechanisms. We identified a novel, CD28-independent mechanism by which CTLA4Ig inhibits activated T cells. We show that in vitro, CTLA4Ig synergizes with NO from bone marrow-derived macrophages to inhibit T cell proliferation. Depletion of regulatory T cells (Tregs) or interference with TGF-beta signaling abrogated the inhibitory effect of CTLA4Ig. Parallel in vivo experiments using an allergic airway inflammation model demonstrated that this novel mechanism required both macrophages and regulatory T cells. Furthermore, CTLA4Ig was ineffective in SMAD3-deficient mice, supporting a requirement for TGF-beta signaling. Thus, in addition to preventing naive T cells from being fully activated, CTLA4Ig can turn off already activated effector T cells by an NO/regulatory T cell/TGF-beta-dependent pathway. This mechanism is similar to cell-extrinsic effects of endogenous CTLA4 and may be particularly important in the ability of CTLA4Ig to treat chronic inflammatory disease.
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