SUBSETS OF HELPER T CELLS IN IMMUNE REGULATION

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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.