SUBSETS OF HELPER T CELLS IN IMMUNE REGULATION

具有Ia特异性受体的自身反应性T细胞克隆已经被发现， 在这个实验室里分离和鉴定。 与抗原不同- 特异性Ia限制性辅助T细胞，这些T细胞克隆是 在缺乏外源性刺激的情况下， 抗原的 自身反应性T细胞在相对较大的 在正常的免疫反应过程中， 选择的外来抗原 我们最近证明了自身反应性T细胞的特异性结合， 在固相测定中将细胞克隆与亲和纯化的Ia结合。 一个主要 这些实验的目的是首次确定 特异性不同T细胞克隆的相对结合亲和力 相同的Ia分子。 我们相信这是可能的，因为T 该测定中的细胞结合是Ia剂量依赖性的。 我们计划， 因此，为了扩大这些研究，以确定相对 不同自身反应性和同种异体反应性T细胞的结合亲合力 I-A和I-E的克隆编码不同来源的分子。 我们将 进一步尝试确定Ia-的实际亲和力常数 特异性T细胞受体通过研究可溶性形式的结合 缺乏疏水跨膜延伸的配体。 截短的分子由L细胞大量分泌 表达重组II类/I类MHC的转染子 大卫博士构建并提供给我们的基因产物 Margulies（免疫学实验室，NIH）。 重组 分子保留了单倍型特异性决定簇， 抗体和T细胞。 由于自身反应性T细胞克隆被Ia阳性细胞激活， 刺激物单独并结合亲和纯化的Ia，它们的受体 对Ia的亲和力必须比 MHC限制性抗原特异性T细胞。 我们将确定 编码这些Ia特异性受体的基因是否 比那些在更大的群体中编码受体的基因多样 MHC限制性抗原特异性辅助性T细胞 如果这被证明 如果是这种情况，那么这种自身Ia特异性T细胞亚群应该 是一个特别有用的“窗口”，通过它来检查 MHC单倍型对生殖系受体基因影响 表情 这是特别的情况，因为独特的 这种T细胞的自身反应特异性将使它们成为 在外周和胸腺中进行选择性扩张。 例如，我们可以确定， 胸腺瘤中选择性表达Ia特异性受体基因 和T细胞白血病或在MHC连锁的Ir基因调节 应答

Autoreactive T cell clones with Ia-specific receptors have been isolated and characterized in this laboratory. Unlike antigen- specific, Ia restricted helper T cells, these T cell clones are activated by syngeneic stimulators in the absence of foreign antigen. autoreactive T cells are induced in relatively large numbers in the course of a normal immune response to randomly chosen foreign antigens. We have recently demonstrated specific binding of autoreactive T cell clones to affinity purified Ia in a solid phase assay. A major goal of these experiments is to determine for the first time the relative binding avidity of different T cell clones specific for the same Ia molecule. We believe this should prove possible since T cell binding in this assay is Ia-dose dependent. We plan, therefore, to extend these studies to determine the relative binding avidity of different autoreactive and alloreactive T cell clones to I-A and I-E encoded molecules of diverse origin. We will further attempt to determine actual affinity constants for Ia- specific T cell receptors by investigating binding of a soluble form of the ligand lacking the hydrophobic transmembrane stretch. The truncated molecule is secreted in large amounts by an L cell transfectant that expresses a recombinant class II/Class I MHC gene product constructed and provided to us by Dr. David Margulies (Laboratory of Immunology, NIH). The recombinant molecule retains haplotype specific determinants recognized by both antibodies and T cells. Since autoreactive T cell clones are activated by Ia-positive stimulators alone and bind to affinity purified Ia, their receptors must have a relatively higher affinity for Ia than receptors of MHC-restricted, antigen-specific T cells. We will determine whether the genes that encode these Ia-specific receptors are less diverse than those that encode receptors in the larger population of MHC-restricted, antigen-specific helper T cells. If this proves to be the case, then this subset of self Ia- specific T cells should be an especially informative "window" through which to examine the influence of MHC-haplotype on germ line receptor gene expression. This is particularly the case as the unique autoreactive specificity of such T cells would make them subject to selective expansion in the periphery as well as in the thymus. It could be determined, for example, whether this same set of self Ia-specific receptor genes is selectively expressed in thymomas and T cell leukemias or in MHC-linked Ir gene regulated responses.