Fallarino F, Fields P E, Gajewski T F
Department of Pathology, The University of Chicago, Chicago, Illinois 60637, USA.
J Exp Med. 1998 Jul 6;188(1):205-10. doi: 10.1084/jem.188.1.205.
Ligation of cytotoxic T lymphocyte antigen 4 (CTLA4) appears to inhibit T cell responses. Four mechanisms have been proposed to explain the inhibitory activity of CTLA4: competition for B7-1 and B7-2 binding by CD28; sequestration of signaling molecules away from CD28 via endocytosis; delivery of a signal that antagonizes a CD28 signal; and delivery of a signal that antagonizes a T cell receptor (TCR) signal. As three of these potential mechanisms involve functional antagonism of CD28, an experimental model was designed to determine whether CTLA4 could inhibit T cell function in the absence of CD28. TCR transgenic/recombinase activating gene 2-deficient/CD28-wild-type or CD28-deficient mice were generated and immunized with an antigen-expressing tumor. Primed T cells from both types of mice produced cytokines and proliferated in response to stimulator cells lacking B7 expression. However, whereas the response of CD28+/+ T cells was augmented by costimulation with B7-1, the response of the CD28-/- T cells was strongly inhibited. This inhibition was reversed by monoclonal antibody against B7-1 or CTLA4. Thus, CTLA4 can potently inhibit T cell activation in the absence of CD28, indicating that antagonism of a TCR-mediated signal is sufficient to explain the inhibitory effect of CTLA4.
细胞毒性T淋巴细胞抗原4（CTLA4）的阻断似乎会抑制T细胞反应。已提出四种机制来解释CTLA4的抑制活性：通过CD28竞争B7-1和B7-2结合；通过内吞作用使信号分子与CD28分离；传递拮抗CD28信号的信号；以及传递拮抗T细胞受体（TCR）信号的信号。由于这些潜在机制中的三种涉及CD28的功能拮抗作用，因此设计了一个实验模型来确定CTLA4在没有CD28的情况下是否能够抑制T细胞功能。构建了TCR转基因/重组酶激活基因2缺陷/CD28野生型或CD28缺陷小鼠，并用表达抗原的肿瘤进行免疫。两种小鼠的致敏T细胞在缺乏B7表达的刺激细胞作用下均产生细胞因子并增殖。然而，虽然CD28+/+T细胞的反应通过与B7-1共刺激而增强，但CD28-/-T细胞的反应却受到强烈抑制。这种抑制作用可被抗B7-1或CTLA4单克隆抗体逆转。因此，CTLA4在没有CD28的情况下能够有效抑制T细胞活化，这表明TCR介导信号的拮抗作用足以解释CTLA4的抑制作用。
