Chirmule N, McCloskey T W, Hu R, Kalyanaraman V S, Pahwa S
Department of Pediatrics, North Shore University Hospital-Cornell University Medical College, Manhasset, NY 11030, USA.
J Immunol. 1995 Jul 15;155(2):917-24.
One mechanism of the immune suppression in HIV infection has been postulated as being caused by the interaction of HIV envelope glycoprotein gp120 with CD4 molecules. Thus, pretreatment of purified peripheral blood T cells or CD4+ T cell clones with gp120 (or an anti-CD4 mAb) results in inhibition of anti-CD3 mAb-induced proliferative responses. In this study, we have analyzed the role of the interacting pairs of costimulatory molecules, CD28-B71 (CD80) and CD40 ligand (CD40L)-CD40, to elucidate further the mechanism of HIV gp120-induced inhibitory effects on T cell functions. Interactions between CD28-B71 and CD40L-CD40 were found to be essential for the anti-CD3 mAb-induced T cell proliferation, as demonstrated by up-regulation of B71 and CD40L and the ability of anti-B71 and anti-CD40L mAbs to inhibit this response. Pretreatment of CD4+ T cells with gp120 before CD3 ligation with anti-CD3 mAb resulted in failure of up-regulation of CD40L on T cells and B71 on APC. Exogenous addition of anti-CD28 mAb overcame the inhibitory effect of gp120 on anti-CD3 mAb-induced T cell proliferation. We conclude that binding of gp120 to CD4 molecules on T cells may interrupt the sequential cascade of intercellular interaction involving 1) Ag/MHC class II-TCR/CD4, 2) CD40L-CD40, and 3) B71-CD28. These studies indicate that the CD4-gp120 interaction results in dysregulation of expression of costimulatory molecules, CD40L, and B71 expression on T cells and APC, respectively, thereby contributing to the T cell hyporesponsiveness in HIV infection.
HIV感染中免疫抑制的一种机制被假定为由HIV包膜糖蛋白gp120与CD4分子相互作用所致。因此，用gp120（或抗CD4单克隆抗体）预处理纯化的外周血T细胞或CD4⁺T细胞克隆会导致抗CD3单克隆抗体诱导的增殖反应受到抑制。在本研究中，我们分析了共刺激分子相互作用对，即CD28 - B71（CD80）和CD40配体（CD40L）- CD40的作用，以进一步阐明HIV gp120诱导的对T细胞功能抑制作用的机制。发现CD28 - B71和CD40L - CD40之间的相互作用对于抗CD3单克隆抗体诱导的T细胞增殖至关重要，这通过B71和CD40L的上调以及抗B71和抗CD40L单克隆抗体抑制该反应的能力得以证明。在用抗CD3单克隆抗体连接CD3之前，先用gp120预处理CD4⁺T细胞，导致T细胞上CD40L和APC上B71无法上调。外源添加抗CD28单克隆抗体克服了gp120对抗CD3单克隆抗体诱导的T细胞增殖的抑制作用。我们得出结论，gp120与T细胞上CD4分子的结合可能会中断细胞间相互作用的顺序级联，该级联包括1）抗原/ MHC II类 - TCR / CD4，2）CD40L - CD40，以及3）B71 - CD28。这些研究表明，CD4 - gp120相互作用分别导致共刺激分子、CD40L以及T细胞和APC上B71表达的失调，从而导致HIV感染中T细胞反应低下。
