Chaturvedi P, Hengeveld R, Zechel M A, Lee-Chan E, Singh B
Department of Microbiology and Immunology, and John P. Robarts Research Institute, University of Western Ontario, London, Ontario N6A 5C1, Canada.
Int Immunol. 2000 Jun;12(6):757-65. doi: 10.1093/intimm/12.6.757.
During the process of class II MHC assembly and cell surface expression, the class II-associated invariant chain peptide (CLIP) is removed from the peptide-binding groove of MHC, a task mediated by H-2M. This allows binding and presentation of peptide epitopes. We have previously shown that exogenously added CLIP interferes with this process and down-regulates the cell surface expression of class II molecules. In this study, we explored the effect of exogenously added CLIP on antigen-specific immune responses. In vivo studies with CLIP and various peptide and protein antigens with different affinities for I-A(d) molecules demonstrated that CLIP variably affects the T cell-mediated immune responses. Immunization with CLIP along with the antigen induced a shift from a T(h)1- to T(h)2-like response as determined by the cytokine profile and antibody isotype. These results suggest that the presence of exogenous CLIP can significantly influence the presentation of antigen by class II MHC molecules to CD4 T cells and thereby modulate immune responses. Exogenously added CLIP rapidly localized into the subcellular compartment of antigen-presenting cells where MHC class II molecules are present. We suggest that exogenous CLIP reduces the loading of peptides on the class II molecules, thus down-regulating MHC-peptide complexes on the cell surface. Alternatively, CLIP may bind to cell surface class II molecules and this complex is rapidly internalized resulting in reduced cell surface MHC class II expression. The reduced level of MHC-peptide complexes favors the activation of T(h)2 cells over T(h)1 cells. These results have implications in the regulation of immune responses, particularly the prevention of certain autoimmune diseases where T(h)1-type responses are pathogenic and T(h)2-type responses are protective.
在II类主要组织相容性复合体（MHC）组装和细胞表面表达过程中，II类相关恒定链肽（CLIP）从MHC的肽结合槽中被移除，这一任务由H - 2M介导。这使得肽表位得以结合和呈递。我们之前已经表明，外源性添加的CLIP会干扰这一过程，并下调II类分子的细胞表面表达。在本研究中，我们探讨了外源性添加的CLIP对抗原特异性免疫反应的影响。对CLIP以及对I - A(d)分子具有不同亲和力的各种肽和蛋白质抗原进行的体内研究表明，CLIP对T细胞介导的免疫反应有不同程度的影响。与抗原一起用CLIP免疫诱导了细胞因子谱和抗体亚型所确定的从Th1样反应向Th2样反应的转变。这些结果表明，外源性CLIP的存在可显著影响II类MHC分子向CD4 T细胞呈递抗原，从而调节免疫反应。外源性添加的CLIP迅速定位于存在II类MHC分子的抗原呈递细胞的亚细胞区室。我们认为，外源性CLIP减少了肽在II类分子上的负载，从而下调了细胞表面的MHC - 肽复合物。或者，CLIP可能与细胞表面的II类分子结合，并且这种复合物会迅速内化，导致细胞表面II类MHC表达降低。MHC - 肽复合物水平的降低有利于Th2细胞而非Th1细胞的激活。这些结果对免疫反应的调节具有重要意义，特别是在预防某些自身免疫性疾病方面，其中Th1型反应具有致病性，而Th2型反应具有保护作用。
