English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

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.

CTLA4Ig Inhibits Effector T Cells through Regulatory T Cells and TGF-β