Physiology and pathophysiology of human Interleukin 12 receptor system

T细胞的激活需要主要组织相容性复合体（MHC）呈递的抗原肽占据T细胞抗原受体（TCR），并通过合适的配体参与共刺激分子。我们对抗原呈递细胞（APC）的抗原呈递机制特别感兴趣。为了解决这个问题，我们开始鉴定在专业APC，树突状细胞（DC）中表达的人类趋化因子受体，并阐明趋化因子受体在抗原呈递中的作用。一些研究者报道了各种趋化因子受体在DC中的信息水平表达。为了在蛋白水平上验证这些观察结果，我们建立了一组C-C和C-X-C型趋化因子受体的单克隆抗体。所有抗体都已被鉴定是否抑制配体诱导的钙动员。所有这些都显示出从生理血细胞中免疫沉淀适当的受体分子。流式细胞术分析显示CCR-1、CCR-3、CCR-5、CCR-6、CCR-7和ccr -4在DC中的表达。在单克隆抗体中，对人CCR-1和CCR-3具有中和性的抗体在跨井迁移分析中可以强烈抑制配体诱导的DC趋化性，这表明与CCR-1和CCR-3共同的配体RANTES是DC的主要趋化剂。出乎意料的是，抑制DC表达的CCR-1和CCR-3会抑制DC对异体T细胞的刺激。抑制的原因可能有几个方面，但观察到的最引人注目的现象是，CCR-1和CCR-3被阻断的DC无法与靶T细胞进行异型聚集，而靶T细胞需要在MHC上安装TCR和肽的接触。

The T cell activation requires occupancy of T cell antigen receptors (TCR) by antigenic peptide presented by Major Histocompatibility Complex (MHC) and engagement of costimulatory molecules by appropriate ligands. We were especially interested in the mechanisms of antigen presentation by antigen presenting cells (APC). To address this issue, we started to identify human chemokine receptors expressed in professional APC, dendritic cells (DC), and to clarify the involvement of chemokine receptors in antigen presentation. Several investigators reported the expression of various chemokine receptors in DC at message level. To verify these observation at protein level, we established monoclonal antibodies to a panel of C-C and C-X-C type chemokine receptors. All antibodies have been characterized whether or not inhibit ligand-induced Ca mobilization. All of them were shown to immunoprecipitate appropriate receptor molecules from physiological blood cells. We could show expression of CCR-1, CCR-3, CCR-5, CCR-6, CCR-7 and CXCR-4 in DC by fiowcytometric analysis. Of monoclonal antibodies, those amtibodies of neutralizing character against human CCR-1 and CCR-3 could strongly inhibit ligand-induced chemotaxis of DC in trans-well migration analysis, which indicates RANTES, a ligand common to CCR-1 and CCR-3 was a major chmoattractant for DC. Inhibition of DC-expressed CCR-1 and CCR-3 resulted, unexpectedly, in inhibition of allogeneic T cell stimulation by DC. The reason for inhibition may be several fold, but the most striking phenomenon observed was that DC whose CCR-1 and CCR-3 were blocked were unable to mount heterotypic aggregation with target T cells required for mounting the contact of TCR and peptide on MHC.