In FY2018 the Retroviral Immunology Section continued investigation into host mechanisms of genetic resistance and susceptibility to retroviral infection. These findings have implications for the design of therapeutics and vaccines to treat and prevent infections with viruses such as HIV. Studies of Friend retrovirus-infected mice revealed a completely new role for B cells outside of their normal antibody-producing and antigen presentation functions. We found that B cells were absolutely required for the induction of regulatory T cell (Treg) responses during infection. Such Treg responses are critical for preventing immunopatholgical damage by overactive immune responses to infectious agents. Experiments showed that a cell surface molecule (GITR-L) expressed on B cells bound to a protein on Tregs (GITR) and delivered an activation signal that allowed the Tregs to respond. In the absence of that signal, the Tregs responded poorly (Moore et al. Bio 2017). We are continuing these studies to develop a more thorough understanding of the B cell subset specifically involved in the support of regulatory T cells. The studies on relationships and interactions between regulatory T cells and B cells led to the finding that regulatory T cells exert potent immunosuppressive effects on B cells and the production of antibodies specific for viral infections. FV induces the activation and expansion of Tregs with suppressive effects on both CD4+ and CD8+ T cells. Depletion of Tregs during FV infection led to elevated activation and class switching of B cells, enhancement of virus-specific and virus-neutralizing antibodies, and significantly reduced viremia. These results demonstrate that Tregs mediate suppression of B cell responses during a live retroviral infection and extends the reach of Treg-mediated suppression to adaptive humoral response (Moore et al. Plos One, 2018). Further experiments studying immunity in the Friend virus model showed that natural or polyreactive antibodies are also under the immunosuppressive control of regulatory T cells. Results from mice deficient in regulatory T cells or depleted of regulatory T cells both indicated that natural antibody titers were significantly higher when regulatory T cell responses were dampened. We are now doing in vivo studies to determine how strong the natural antibody response is in protection against viral and bacterial infections and whether such antibodies might be used therapeutically, especially in terms of protection against antibiotic resistant strains of bacteria. Major advances have been made in examining the role of SIRP alpha in marking the functional subset of virus-specific CD8+ T cells present in chronically infected animals and humans. We have found that not all CD8+ T cells in chronic infections are exhausted and that residual functional cells express SIRP alpha, a molecule previously thought to be only expressed by myeloid cells, stem cells and neurons. The manuscript is under second review at Nature Communications.
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