Oosterwegel M A, Mandelbrot D A, Boyd S D, Lorsbach R B, Jarrett D Y, Abbas A K, Sharpe A H
Immunology Research Division, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
J Immunol. 1999 Sep 1;163(5):2634-9.
To examine the role of CTLA-4 in Th cell differentiation, we used two newly generated CTLA-4-deficient (CTLA-4-/-) mouse strains: DO11. 10 CTLA-4-/- mice carrying a class II restricted transgenic TCR specific for OVA, and mice lacking CTLA-4, B7.1 and B7.2 (CTLA-4-/- B7.1/B7.2-/- ). When purified naive CD4+ DO11.10 T cells from CTLA-4-/- and wild-type mice were primed and restimulated in vitro with peptide Ag, CTLA-4-/- DO11.10 T cells developed into Th2 cells, whereas wild-type DO11.10 T cells developed into Th1 cells. Similarly, when CTLA-4-/- CD4+ T cells from mice lacking CTLA-4, B7. 1, and B7.2 were stimulated in vitro with anti-CD3 Ab and wild-type APC, these CTLA-4-/- CD4+ T cells produced IL-4 even during the primary stimulation, whereas CD4+ cells from B7.1/B7.2-/- mice did not produce IL-4. Upon secondary stimulation, CD4+ T cells from CTLA-4-/- B7.1/B7.2-/- mice secreted high levels of IL-4, whereas CD4+ T cells from B7.1/B7.2-/- mice produced IFN-gamma. In contrast to the effects on CD4+ Th differentiation, the absence of CTLA-4 resulted in only a modest effect on T cell proliferation, and increased proliferation of CTLA-4-/- CD4+ T cells was seen only during secondary stimulation in vitro. Administration of a stimulatory anti-CD28 Ab in vivo induced IL-4 production in CTLA-4-/- B7.1/B7.2-/- but not wild-type mice. These studies demonstrate that CTLA-4 is a critical and potent inhibitor of Th2 differentiation. Thus, the B7-CD28/CTLA-4 pathway plays a critical role in regulating Th2 differentiation in two ways: CD28 promotes Th2 differentiation while CTLA-4 limits Th2 differentiation.
为了研究CTLA-4在Th细胞分化中的作用，我们使用了两种新构建的CTLA-4缺陷（CTLA-4-/-）小鼠品系：携带针对OVA的II类限制性转基因TCR的DO11.10 CTLA-4-/-小鼠，以及缺乏CTLA-4、B7.1和B7.2的小鼠（CTLA-4-/- B7.1/B7.2-/-）。当用肽抗原在体外对来自CTLA-4-/-和野生型小鼠的纯化幼稚CD4+ DO11.10 T细胞进行初次刺激和再刺激时，CTLA-4-/- DO11.10 T细胞分化为Th2细胞，而野生型DO11.10 T细胞分化为Th1细胞。同样，当用抗CD3抗体和野生型抗原呈递细胞在体外刺激来自缺乏CTLA-4、B7.1和B7.2的小鼠的CTLA-4-/- CD4+ T细胞时，这些CTLA-4-/- CD4+ T细胞即使在初次刺激期间也产生IL-4，而来自B7.1/B7.2-/-小鼠的CD4+细胞不产生IL-4。再次刺激后，来自CTLA-4-/- B7.1/B7.2-/-小鼠的CD4+ T细胞分泌高水平的IL-4，而来自B7.1/B7.2-/-小鼠的CD4+ T细胞产生IFN-γ。与对CD4+ Th分化的影响相反，CTLA-4的缺失对T细胞增殖仅产生适度影响，并且仅在体外再次刺激期间观察到CTLA-4-/- CD4+ T细胞增殖增加。在体内给予刺激性抗CD28抗体可诱导CTLA-4-/- B7.1/B7.2-/-小鼠而非野生型小鼠产生IL-4。这些研究表明CTLA-4是Th2分化的关键且强效的抑制剂。因此，B7-CD28/CTLA-4途径通过两种方式在调节Th2分化中起关键作用：CD28促进Th2分化而CTLA-4限制Th2分化。
