Phelps R G, Jones V L, Coughlan M, Turner A N, Rees A J
Department of Medicine and Therapeutics, University of Aberdeen, Foresterhill, Aberdeen, AB25 2ZD, Scotland, United Kingdom.
J Biol Chem. 1998 May 8;273(19):11440-7. doi: 10.1074/jbc.273.19.11440.
Class II molecules are believed to influence immune responses by selectively binding antigen-derived peptides for recognition by T cells. In Goodpasture's (anti-glomerular basement membrane) disease, autoimmunity to the NC1 domain of the alpha3-chain of type IV collagen (alpha3(IV)NC1) is strongly associated with HLA-DR15. We have examined the influence of the peptide binding preferences of DR15 molecules on the selection of alpha3(IV)NC1-derived peptides displayed bound to DR15 molecules on the surface of alpha3(IV)NC1-pulsed DR15-homozygous Epstein-Barr virus-transformed human B cells. The preferences of DR15 molecules were investigated using a panel of 24 overlapping peptides spanning the sequence of alpha3(IV)NC1. The alpha3(IV)NC1-derived peptides selected for display to T cells were determined by biochemical analysis as reported previously (Phelps, R. G., Turner, A. N., and Rees, A. J. (1996) J. Biol. Chem. 271, 18549-18553). Three nested sets of naturally presented alpha3(IV)NC1 peptides were detectable bound to DR15 molecules. Peptides representative of each nested set bound to DR15 molecules, but almost two-thirds of the alpha3(IV)NC1 peptides studied had as good or better DR15 affinity than those identified as naturally processed. Thus alpha3(IV)NC1 presentation to T cells is determined more by "processing factors" than by the preferences of relatively indiscriminate DR15 molecules. The results have important implications for the use of class II peptide binding data to aid identification of potential T cell epitopes, especially for antigens which, like alpha3(IV)NC1, contain many sequences able to bind class II molecules.
II类分子被认为通过选择性结合抗原衍生肽以供T细胞识别来影响免疫反应。在Goodpasture病（抗肾小球基底膜病）中，针对IV型胶原α3链的NC1结构域（α3(IV)NC1）的自身免疫与HLA-DR15密切相关。我们研究了DR15分子的肽结合偏好对α3(IV)NC1脉冲处理的DR15纯合型爱泼斯坦-巴尔病毒转化的人B细胞表面与DR15分子结合展示的α3(IV)NC1衍生肽选择的影响。使用一组覆盖α3(IV)NC1序列的24个重叠肽研究了DR15分子的偏好。如先前报道（Phelps, R. G., Turner, A. N., and Rees, A. J. (1996) J. Biol. Chem. 271, 18549 - 18553），通过生化分析确定了选择用于向T细胞展示的α3(IV)NC1衍生肽。可检测到三组嵌套的天然呈递的α3(IV)NC1肽与DR15分子结合。代表每个嵌套组的肽与DR15分子结合，但所研究的α3(IV)NC1肽中近三分之二对DR15的亲和力与那些被鉴定为天然加工的肽一样好或更好。因此，α3(IV)NC1向T细胞的呈递更多地由“加工因子”决定，而非相对不加选择的DR15分子的偏好。这些结果对于利用II类肽结合数据辅助鉴定潜在T细胞表位具有重要意义，特别是对于像α3(IV)NC1这样包含许多能够结合II类分子序列的抗原。
