ROLE OF AUTOREACTIVE T CELLS IN MURINE AIDS

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In the murine acquired immunodeficiency syndrome (MAIDS), an animal model, in certain aspects, for AIDS, C57BL/6 mice are infected with a mixture of ecotropic and replication defective murine leukemia virus strains. This infection causes rapid proliferation of lymphoid cells leading to lymphadenopathy, splenomegaly, hypergammaglobulinemia, and followed by profound immunosuppression affecting all aspects of cellular and humoral immunity. The mechanism(s) of pathogenesis remains unclear. We have recently demonstrated that rat CD4+ auto-reactive T cell lines and clones (ATs) proliferate specifically in response to syngeneic B cells. Moreover, when normal B cells are cultured with tau-irradiated ATs, B cells proliferate and differentiate into IgM/IgG producing cells. Furthermore, injection of ATs into syngeneic hosts results in splenomegaly and hypergammaglobulinemia. Also, ATs can trigger the proliferation of naive CD4+ and CD8+ T cells, the resulting anti-idiotypic cell lines are designated AATs. Because there are clear similarities between the immunological effects of ATs and early stages of MAIDS and AIDS, this proposal is directed to determine: (a) whether autoimmunity and immunosuppression associated with MAIDS are mediated through the induction of ATs- To achieve this goal, we will determine whether MAIDS increases the frequency of B cell-reactive ATs and if reconstitution of irradiated animals with AT-depleted splenic lymphocytes will alter the course of MAIDS. In addition, using northern blot analysis, we will investigate whether CD4+ T cells, arising in MAIDS, like ATs, have a restricted T cell receptor heterogeneity, and (b) whether AATs regulate the activity of ATs- The effects of AATs on AT-induced proliferation and differentiation of B cells in vitro, induction of splenomegaly, and hypergammaglobulinemia in vivo will be tested. These studies should lead to a better understanding of the mechanism(s) of retrovirus-induced autoimmunity and immunosuppression. This will enable rational approaches for AIDS therapies.