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 在本实验室进行分离和鉴定。与抗原不同- 特定的Ia限制性辅助T细胞，这些T细胞克隆是 在没有外源基因的情况下由同基因刺激物激活 抗原。在相对较大的细胞中诱导自身反应性T细胞 正常免疫反应过程中的数字随机 选定的外来抗原。 我们最近证实了自身反应性T细胞的特异性结合。 固相亲和纯化Ia的细胞克隆。一位少校 这些实验的目标是首次确定 不同特异性T细胞克隆的相对结合亲和力 相同的Ia分子。我们相信这应该是可能的，因为T 本实验中的细胞结合是Ia剂量依赖性的。我们计划， 因此，扩展这些研究以确定相对 不同自身反应性和异体反应性T细胞的结合亲和力 I-A和I-E的克隆编码不同来源的分子。我们会 进一步尝试确定Ia-的实际亲和常数 通过研究可溶性形式的结合来研究特异性T细胞受体 缺乏疏水跨膜拉伸的配体。 截短的分子由L细胞大量分泌 表达重组II/I类MHC的转染体 大卫博士构建并提供给我们的基因产品 马古利斯(美国国立卫生研究院免疫学实验室)重组人 分子保留单倍型识别的特定决定因素 抗体和T细胞。 由于自身反应性T细胞克隆被Ia阳性激活 单独刺激并与亲和纯化的Ia及其受体结合 对Ia的亲和力必须比Ia受体相对更高 受MHC限制的抗原特异性T细胞。我们将决定 编码这些Ia特异性受体的基因是否更少 在更大的人群中比编码受体的基因更多样化 MHC限制性抗原特异性辅助性T细胞。如果这能证明 在这种情况下，这个自身Ia特异性T细胞的子集应该 成为一个信息量特别大的“窗口”，通过它来检查 MHC单倍型对生殖系受体基因的影响 表情。尤其是作为独一无二的 这种T细胞的自身反应性使它们成为 在外周和胸腺有选择地扩张。 例如，可以确定这组相同的自我 胸腺瘤中IA特异性受体基因的选择性表达 和T细胞白血病或在MHC连锁ir基因中调节 回应。

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.