CTLA4Ig inhibits effector T cells through regulatory T cells and TGF-β

Christine M. Deppong, Traci L. Bricker, Brandy D. Rannals, Nico Van Rooijen, Chyi Song Hsieh, Jonathan M. Green

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


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-b 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-b 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-b-dependent pathway. This mechanism is similar to cellextrinsic effects of endogenous CTLA4 and may be particularly important in the ability of CTLA4Ig to treat chronic inflammatory disease.

Original languageEnglish
Pages (from-to)3082-3089
Number of pages8
JournalJournal of Immunology
Issue number6
StatePublished - Sep 15 2013


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