MOLECULAR LOCALIZATION AND POLYMORPHISM OF HLA CLASS-II RESTRICTION DETERMINANTS DEFINED BY MYCOBATERIUM-LEPRAE-REACTIVE HELPER T-CELL CLONES FROM LEPROSY PATIENTS
MOLECULAR LOCALIZATION AND POLYMORPHISM OF HLA CLASS-II RESTRICTION DETERMINANTS DEFINED BY MYCOBATERIUM-LEPRAE-REACTIVE HELPER T-CELL CLONES FROM LEPROSY PATIENTS
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DOI：
10.1084/jem.164.6.1923
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发表时间：
1986-12-01
影响因子：
15.3
通讯作者：
DEVRIES, RRP
中科院分区：
文献类型：
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作者：
OTTENHOFF, THM;NEUTEBOOM, S;DEVRIES, RRP
MHC II类分子携带限制性决定簇(RD)，用于将抗原呈递给抗原特异性的Th淋巴细胞。这种对T细胞激活的限制赋予了这些分子在诱导和调节抗原特异性免疫反应方面的关键作用。此外，第II类分子是第II类免疫反应(Ir)基因的产物。这些ir基因的多态性导致了不同个体之间免疫反应的遗传控制差异。一个重要的人类例子是麻风病，在这种情况下，人类白细胞抗原II类连接的ir基因决定了对麻风分枝杆菌的免疫反应，麻风分枝杆菌是麻风病的病原体。由于麻风支原体的免疫应答完全依赖于Th细胞，因此，HLAII类Ir基因产物可以通过控制麻风支原体抗原递呈给Th细胞来很好地调节免疫应答。因此，我们对麻风杆菌反应性Th细胞克隆(TLC)的HLAII类RD谱系进行了研究，方法是对完全II型同种异体APC和明确定义的HLAII类特异性单抗进行广泛的小组和抑制研究。所研究的TLC(n，36)向麻风杆菌特异增殖，产生干扰素-γ。激活后，具有CD3+CD4+CD8-表型。结果表明，麻风杆菌的RDS主要分布在DR上，而不是Dp或DQ分子上。这表明DR分子在麻风杆菌免疫反应中起主要作用，并表明这些分子是麻风杆菌特异性ir基因的主要产物。此外，由于DR分子的表达比DP和DQ分子强得多，这些发现表明麻风杆菌RDS在II类分子上的定位与这些分子的定量表达有关。观察到由DR4单倍型编码的RD儿子DR分子只位于已知表达最高的DR分子上，这一观察结果也可以用同样的方式解释。第二，DR4Dw13单倍型的DR+DR 253-(α...β1)分子携带了与Dw13同种决定簇相关但不完全相同的四个不同的RDS。由于已知的与DR4相关的Dw.beta.1链之间的氨基酸残基差异不能解释观察到的RD多态，这一观察表明这些分子表达了DR4Dw13单倍型特有的多个不同的RD。在36个TLC中，只有2个没有受到DR的限制，其中一个TLC识别了一个新的DP决定簇，而另一个TLC在DQ分子上定义了一个显著多态的RD，这与已知的DQ相关同种异体特异性不同。因此，这些TLC定义了II类分子上新的和功能相关的多态。最后，在36个TLC中，有3个在没有麻风杆菌抗原的情况下也与数量有限的同种异体APC反应，这表明自身II类RD与麻风杆菌抗原和同种异体决定簇之间存在交叉反应。
MHC class II molecules carry the restriction determinants (RDs) for antigen presentation to antigen-specific Th lymphocytes. This restriction of T cell activation endows those molecules with a key role in the induction and regulation of antigen-specific immune responses. Moreover, class II molecules are the products of class II immune response (Ir) genes. The polymorphism of these Ir genes leads to genetically controlled differences in immuneresponsiveness between different individuals. An important human example is leprosy, in which HLA class II-linked Ir genes determine the immune response against Mycobacterium leprae, the causative organism of the disease. Since the immune response against M. leprae is entirely dependent on Th cells, the HLA class II-linked Ir gene products may well regulate the immune response by controlling the presentation of M. leprae antigens to Th cells. We therefore have investigated the HLA class II RD repertoire of M. leprae-reactive Th cell clones (TLC) by means of extensive panel and inhibition studies with fully class II-typed allogeneic APCs and well-defined HLA class II-specific mAbs. The TLC studied (n, 36) proliferated speficially towards M. leprae, produced IFN-.gamma. upon activation, and had the CD3+ CD4+ CD8- phenotype. The results show in the first place that the majority of the RDs for M. leprae reside on DR and not on DP or DQ molecules. This indicates a major role for DR molecules in the immune response to M. leprae and suggests that these molecules are the main products of M. leprae-specific Ir genes. Furthermore, since the expression of DR molecules is much stronger than that of DP and DQ molecules, these findings suggest that the localization of RDs for M. leprae on class II molecules correlates with the quantitative expression of these molecules. The observation that the RD son DR molecules coded by a DR4 haplotype were situated only on those DR molecules that are known to be highest in expression can be explained in the same way. Second, four distinct RDs related with but not identical to the Dw13 allodeterminant were carried by the DR+DR 253- (.alpha..beta.1) molecules of a DR4Dw13 haplotype. Since the known amino acid residue differences between the allelic DR4 related Dw.beta.1 chains cannot explain the observed RD-polymorphism, this observation suggests that multiple distinct RDs unique for the DR4Dw13 haplotype are expressed by these molecules. Only 2 of 36 TLC were not restricted by DR. One of these TLC recognized a new DP determinant, whereas the other TLC defined a remarkably polymorphic RD on a DQ molecule, which was distinct from the known DQ-related allospecificities. These TLC therefore define novel and functionally relevant polymorphisms on class II molecules. Finally, 3 of the 36 TLC reacted also with a restricted number of allogeneic APC in the absence of M. leprae antigen, indicating crossreactivity between self class II RD in combination with M. leprae antigens and allodeterminants.