NZB mice are an animal model widely used for investigations into the pathogenesis of autoimmunity. The primary focus of this laboratory has been on understanding T cell immune responses and T cell regulatory defects in these autoimmune mice. In this proposal our goal is the cellular and molecular characterization of a recently observed defect in T cell immunoregulation by NZB spleen cells and to determine the relationship of this defect to the pathogenesis of their autoimmune disease. The project is based on two sets of preliminary data. The first is that the unusual ability of NZB spleen cells to mount primary anti-Qa-1 cytotoxic lymphocyte (CTL) responses during H-2-identical mixed leukocyte culture (MLC) is due to their deficiency of a radiosensitive, Thy- 1+, Lyt-1+, Lyt-2-, L3T4+ T cell subpopulation. The second is that deletion of this subpopulation from normal mice also enables the normal spleen cells to mount primary CTL responses during H- 2d-identical, Qa-1 disparate MLC. The capacity to induce spleen cells from normal mice to mount an immune response previously limited to NZB cells provides the exciting potential to assess the role of this NZB regulatory defect on the pathogenesis of their disease. With this model system we have also provided the first evidence that primary CTL responses to Qa/Tla-region encoded class I alloantigens is under T suppressor cell regulation.
The aims of this proposal are to: 1) characterize the synergistic cellular interactions involved in suppression by these L3t4+ cells, ii) investigate the nature and ontogeny of the L3T4+cellular defect in NZB mice, iii) develop L3T4+ cell lines and clones which mediate suppression, and iv) employ radiation chimeras to investigate the relationship of the L3T4+ subpopulation deficiency to autoimmunity. These studies will employ cell mixing experiments, positive and negative selection procedures for lymphocyte subpopulations, flow cytometry, modulation of cell surface molecules with monoclonal antibodies, and T cell cloning techniques. Monoclonal antibodies which recognize subsets of thymocytes, and were developed in this lab from NZB mice spontaneously seropositive for anti-thymocyte antibodies, will be used to more precisely define, isolate and clone the L3T4+ cells under study. Radiation chimeras reconstituted with mixtures of NZB and normal H-2d T cells and non-T cells will be studied for production of autoantibodies and for impaired tolerance. Utilizing this model, these studies should advance our understanding of physiologic regulatory T cell interactions and provide insight into pathogenic immunoregulatory defects in autoimmune diseases.
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