DISRUPTION OF THE DETERMINANT HIERARCHY ON A SELF-MHC PEPTIDE - CONCOMITANT TOLERANCE INDUCTION TO THE DOMINANT DETERMINANT AND PRIMING TO THE CRYPTIC SELF-DETERMINANT
DISRUPTION OF THE DETERMINANT HIERARCHY ON A SELF-MHC PEPTIDE - CONCOMITANT TOLERANCE INDUCTION TO THE DOMINANT DETERMINANT AND PRIMING TO THE CRYPTIC SELF-DETERMINANT
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DOI：
10.1093/intimm/6.1.131
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发表时间：
1994-01-01
影响因子：
4.4
通讯作者：
SERCARZ, EE
中科院分区：
文献类型：
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作者：
BENICHOU, G;FEDOSEYEVA, E;SERCARZ, EE
自我肽以自我限制的方式呈递在T细胞识别自我决定簇的复杂的正选择性和负选择性过程中起着关键作用。所述决定簇群体包含（i）显性组，其被有效呈递并诱导相应的自身反应性T细胞的克隆消除或失活，和（ii）隐蔽组，其未被足够有效地处理以达到呈递阈值，从而在胸腺选择期间对T细胞库产生影响。在这里，我们研究了自身MHC肽，L（d）61-85，如在早期的工作中所示，它能够诱导同基因动物中的T细胞增殖。尽管该肽作为一个整体是“神秘的”，但II类限制性应答的精细特异性是复杂的，因为存在三种不同且重叠的T细胞决定簇：显性决定簇L（d）65-80，两侧是两个隐蔽决定簇L（d）61-15和L（d）73-85，它们都竞争刺激体内自身反应性T细胞增殖反应。这些决定因素的层次结构与容忍度有着有趣的关系。L（d）61-85或L（d）61-80引发仅诱导对L（d）65-80的增殖;同样，对L（d）61-80的耐受性诱导防止在局部淋巴结中引发对L（d）61-80或L（d）65-80的后续应答。然而，在L（d）61-80耐受小鼠中，用L（d）61-80的体内攻击诱导针对隐蔽的L（d）61-75的强T细胞增殖应答。显然，虽然耐受性已被诱导到显性自身决定簇，同时引发发生的隐蔽决定簇，使其可见和免疫原性。耐受诱导逆转了优势等级，这一结果对自身免疫有重要影响。
The presentation of self-peptides in a self-restricted manner plays a critical role in the complex positive and negative selective process of T cell recognition of self-determinants. The population of determinants comprises (i) a dominant set which is efficiently presented and induces clonal elimination or inactivation of the corresponding autoreactive T cells, and (ii) a cryptic set which is not processed efficiently enough to reach the threshold of presentation to make an impact on the T cell repertoire during thymic selection. Here we have studied a self-MHC peptide, L(d) 61-85, which as shown in earlier work was able to induce vigorous T cell proliferation in syngeneic animals. Despite the fact that this peptide as a whole is 'cryptic', the fine specificity of the class II restricted response was complex, in that there were three distinct and overlapping T cell determinants: the dominant determinant, L(d) 65-80, flanked by two cryptic determinants, L(d) 61-15 and L(d) 73-85, all of which compete for stimulating in vivo autoreactive T cell proliferative responses. The hierarchy of these determinants bears an interesting relationship to tolerance. L(d) 61-85 or L(d) 61-80 priming induces proliferation only to L(d) 65-80; likewise, tolerance induction to L(d) 61-80 prevents elicitation of a subsequent response to L(d) 61-80 or L(d) 65-80 in the local lymph nodes. However, in the L(d) 61-80 tolerant mice, in vivo challenge with L(d) 61-80 induces a strong T cell proliferative response directed towards cryptic L(d) 61-75. Apparently, while tolerance had been induced to the dominant self-determinant, simultaneous priming occurred to the cryptic determinant, making it visible and immunogenic. Tolerance induction had reversed the hierarchy of dominance, a consequence that has important ramifications for autoimmunity.