EXPRESSION AND FUNCTION OF CTLA-4 IN TH1 AND TH2 CELLS

CTLA-4 is expressed on T cells after activation and shares homology wi th the CD28 costimulatory receptor. In contrast to CD28, CTLA-4 is tho ught to be a negative regulator of T cell activation. Cross-linking of CTLA-4 during activation of peripheral T cells reduces IL-2 productio n and arrests T cells in G1. Much less is known about the function of CTLA-4 in differentiated T cells. We have investigated the expression and function of CTLA-4 in established Th1 and Th2 clones and in bulk p opulations of Th1 and Th2 cells freshly derived in vitro from TCR tran sgenic splenocytes. We found that CTLA-4 was induced under similar con ditions and with similar kinetics following activation of both Th1 and Th2 clones, However, CTLA-4 expression was much higher in Th2 than Th 1 clones and lines. This was confirmed by how cytometry, confocal micr oscopy, and Northern blot analysis. The ratio of surface to intracellu lar expression of CTLA-4 and its rate of endocytosis were similar in T h1 and Th2 clones, Inhibition of binding of CTLA-4 to its ligands usin g soluble anti-CTLA-4 mAb during stimulation with Ag increased the pro duction not only of IL-2 by Th1 clones, but also that of IL-3 and IFN- gamma by Th1 clones and of IL-3, IL-4, IL-5, and IL-10 by Th2 clones. In contrast, when anti-CTLA-4 was coimmobilized with anti-CDS and anti -CD28 mAbs, a decrease in the production of multiple cytokines was obs erved. We conclude that CTLA-4 can function to suppress the production of cytokines produced by both Th1 and Th2 cells.