B7-1 engagement of cytotoxic T lymphocyte antigen 4 inhibits T cell activation in the absence of CD28.
B7-1 engagement of cytotoxic T lymphocyte antigen 4 inhibits T cell activation in the absence of CD28.
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DOI：
10.1084/jem.188.1.205
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发表时间：
1998-07-06
期刊：
影响因子：
--
通讯作者：
Gajewski TF
中科院分区：
文献类型：
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作者：
Fallarino F;Fields PE;Gajewski TF
细胞毒性T淋巴细胞抗原4 （CTLA4）的结扎似乎抑制T细胞反应。CTLA4的抑制活性被提出了四种机制：CD28对B7-1和B7-2结合的竞争；通过内吞作用将信号分子从CD28上隔离；传递拮抗CD28信号的信号；以及拮抗T细胞受体（TCR）信号的信号传递。由于这些潜在机制中有三种涉及CD28的功能性拮抗，因此设计了一个实验模型来确定CTLA4是否可以在缺乏CD28的情况下抑制T细胞功能。制备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免疫。两种小鼠的启动T细胞对缺乏B7表达的刺激细胞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的共刺激而增强，但CD28−/−T细胞的反应被强烈抑制。这种抑制作用被抗B7-1或CTLA4的单克隆抗体逆转。因此，CTLA4可以在缺乏CD28的情况下有效抑制T细胞活化，这表明tcr介导的信号拮抗足以解释CTLA4的抑制作用。
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.