Wu Y, Xu J, Shinde S, Grewal I, Henderson T, Flavell R A, Liu Y
Michael Heidelberger Division of Immunology, Department of Pathology, New York University Medical Center, New York 10016, USA.
Curr Biol. 1995 Nov 1;5(11):1303-11. doi: 10.1016/s0960-9822(95)00257-0.
T cells and B cells communicate by direct cell--cell interaction that is crucial to the functioning of the immune system. It is well established that the interaction between B-cell-expressed CD40 and T-cell-expressed CD40 ligand (CD40L) is critical for T-cell-dependent antibody responses, but the role of this interaction in T-cell responses is less clear. In this study, we have used mice with targeted mutations in the genes encoding CD40L or CD28 to investigate how the CD40-CD40L interaction induces on B cells a costimulatory activity that acts in addition to antigen to trigger T-cell growth.
We show that T cells from Cd40L-deficient mice induce a substantially reduced costimulatory activity on B cells compared to wild-type T cells, particularly at early time points. Surprisingly, T cells, from CD40L-deficient mice induce similar levels of B7-1 and B7-2 as do wild-type T cells. We further show that the CD40L-mediated induction of costimulatory activity precedes the induction of B7-1, B7-2 and the heat-stable antigen (HSA). CD4 T cells isolated from the CD28-deficient mice can receive costimulatory activity from CD40L-induced B cells, demonstrating that the induced molecules can costimulate T cells by a CD28-independent mechanism. We have generated a novel monoclonal antibody that inhibits the CD40L-induced costimulatory activity. Expression of the epitope detected by this monoclonal antibody correlates with the induction of the costimulatory activity, and the molecule recognized by the monoclonal antibody is a single chain of around 85 kDa, distinct from B7-1, B7-2, ICAM-1, ICAM-2, ICAM-3, HSA CD5, integrin and 4-1BB ligand.
Our results demonstrate that CD40L is both necessary and sufficient for rapid, T-cell-mediated induction of costimulatory activity on B cells. This costimulatory activity is distinct from B7-1 and B7-2, and is independent of CD28.
T细胞和B细胞通过直接的细胞间相互作用进行通讯，这种相互作用对免疫系统的功能至关重要。众所周知，B细胞表达的CD40与T细胞表达的CD40配体（CD40L）之间的相互作用对于T细胞依赖性抗体反应至关重要，但这种相互作用在T细胞反应中的作用尚不清楚。在本研究中，我们使用了编码CD40L或CD28基因发生靶向突变的小鼠，以研究CD40-CD40L相互作用如何在B细胞上诱导一种共刺激活性，该活性除抗原外还能触发T细胞生长。
我们发现，与野生型T细胞相比，来自Cd40L缺陷小鼠的T细胞在B细胞上诱导的共刺激活性显著降低，尤其是在早期时间点。令人惊讶的是，来自CD40L缺陷小鼠的T细胞诱导的B7-1和B7-2水平与野生型T细胞相似。我们进一步表明，CD40L介导的共刺激活性诱导先于B7-1、B7-2和热稳定抗原（HSA）的诱导。从CD28缺陷小鼠中分离的CD4 T细胞可以从CD40L诱导的B细胞接受共刺激活性，这表明诱导的分子可以通过不依赖CD28的机制共刺激T细胞。我们制备了一种新型单克隆抗体，它能抑制CD40L诱导的共刺激活性。该单克隆抗体检测到的表位表达与共刺激活性的诱导相关，并且该单克隆抗体识别的分子是一条约85 kDa的单链，不同于B7-1、B7-2、ICAM-1、ICAM-2、ICAM-3、HSA、CD5、整合素和4-1BB配体。
我们的结果表明，CD40L对于T细胞介导的B细胞共刺激活性的快速诱导既是必需的也是充分的。这种共刺激活性不同于B7-1和B7-2，且不依赖于CD28。
