title: CTLA4Ig inhibits effector T cells through regulatory T cells and TGF-β.
abstract: 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-β 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-β 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-β-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.
authors: Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors: Christine M
authors: CM
authors: Deppong
authors: Traci L
authors: TL
authors: Bricker
authors: Brandy D
authors: BD
authors: Rannals
authors: Nico
authors: N
authors: Van Rooijen
authors: Chyi-Song
authors: CS
authors: Hsieh
authors: Jonathan M
authors: JM
authors: Green
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D060908:CTLA-4 Antigen / Q000276:immunology*; D018920:Coculture Techniques; D004195:Disease Models, Animal; D005434:Flow Cytometry; D018796:Immunoconjugates / Q000494:pharmacology; D007074:Immunoglobulin G / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D008264:Macrophages; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D012130:Respiratory Hypersensitivity / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000276:immunology*
chemical_list: D000893:Anti-Inflammatory Agents; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta
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