Foy T M, Page D M, Waldschmidt T J, Schoneveld A, Laman J D, Masters S R, Tygrett L, Ledbetter J A, Aruffo A, Claassen E, Xu J C, Flavell R A, Oehen S, Hedrick S M, Noelle R J
Department of Microbiology, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA.
J Exp Med. 1995 Nov 1;182(5):1377-88. doi: 10.1084/jem.182.5.1377.
The interactions between CD40 on B cells and its ligand gp39 on activated T helper cells are known to be essential for the development of thymus-dependent humoral immunity. However, CD40 is also functionally expressed on thymic epithelial cells and dendritic cells, suggesting that gp39-CD40 interactions may also play a role in thymic education, the process by which self-reactive cells are deleted from the T cell repertoire. Six systems of negative selection were studied for their reliance on gp39-CD40 interactions to mediate negative selection. In all cases, when the antigen/superantigen was endogenously expressed (in contrast to exogenously administered), negative selection was blocked by loss of gp39 function. Specifically, blockade of gp39-CD40 interactions prevented the deletion of thymocytes expressing V beta 3, V beta 11, and V beta 12, specificities normally deleted in BALB/c mice because of the endogenous expression of minor lymphocyte-stimulating determinants. Independent verification of a role of gp39 in negative selection was provided by studies in gp39-deficient mice where alterations in T cell receptor (TCR) V beta expression were also observed. Studies were also performed in the AND TCR transgenic (Tg) mice, which bear the V alpha 11, V beta 3 TCR and recognize both pigeon cytochrome c (PCC)/IEk and H-2As. Neonatal administration of anti-gp39 to AND TCR Tg mice that endogenously express H-2As or endogenously produce PCC prevented the deletion of TCR Tg T cells. In contrast, deletion mediated by high-dose PCC peptide antigen (administered exogenously) in AND TCR mice was unaltered by administration of anti-gp39. In addition, deletion by Staphylococcus enterotoxin B in conventional mice was also unaffected by anti-gp39 administration. gp39 expression was induced on thymocytes by mitogens or by antigen on TCR Tg thymocytes. Immunohistochemical analysis of B7-2 expression in the thymus indicated that, in the absence of gp39, B7-2 expression was substantially reduced. Taken together, these data suggest that gp39 may influence negative selection through the regulation of costimulatory molecule expression. Moreover, the data support the hypothesis that, for negative selection to some endogenously produced antigens, negative selection may be dependent on TCR engagement and costimulation.
已知B细胞上的CD40与其配体——活化的辅助性T细胞上的gp39之间的相互作用对于胸腺依赖性体液免疫的发展至关重要。然而，CD40在胸腺上皮细胞和树突状细胞上也有功能性表达，这表明gp39-CD40相互作用可能在胸腺细胞教育过程中也发挥作用，胸腺细胞教育是指从T细胞库中清除自身反应性细胞的过程。研究了六个阴性选择系统对gp39-CD40相互作用介导阴性选择的依赖性。在所有情况下，当抗原/超抗原内源性表达时（与外源性给予相反），gp39功能丧失会阻断阴性选择。具体而言，阻断gp39-CD40相互作用可阻止表达Vβ3、Vβ11和Vβ12的胸腺细胞的清除，由于次要淋巴细胞刺激决定簇的内源性表达，这些特异性在BALB/c小鼠中通常会被清除。在gp39缺陷小鼠中的研究提供了gp39在阴性选择中作用的独立验证，在这些小鼠中也观察到了T细胞受体（TCR）Vβ表达的改变。研究还在AND TCR转基因（Tg）小鼠中进行，这些小鼠携带Vα11、Vβ3 TCR，可识别鸽细胞色素c（PCC）/IEk和H-2As。对内源性表达H-2As或内源性产生PCC的AND TCR Tg小鼠新生期给予抗gp39可阻止TCR Tg T细胞的清除。相比之下，在AND TCR小鼠中，高剂量PCC肽抗原（外源性给予）介导的清除不受抗gp39给予的影响。此外，在常规小鼠中，葡萄球菌肠毒素B介导的清除也不受抗gp39给予的影响。丝裂原或TCR Tg胸腺细胞上的抗原可诱导胸腺细胞表达gp39。胸腺中B7-2表达的免疫组织化学分析表明，在缺乏gp39的情况下，B7-2表达显著降低。综上所述，这些数据表明gp39可能通过调节共刺激分子的表达来影响阴性选择。此外，数据支持这样一种假设，即对于某些内源性产生的抗原的阴性选择，阴性选择可能依赖于TCR结合和共刺激。
