The CD4+ T cell response to CNS viral infection

T cell-mediated pathology is a major cause of disease in both infection and autoimmunity. While T cell responses provide protection from pathogens, uncontrolled responses can lead to rampant autoimmunity and immunopathology. In this dissertation, we employed a mouse model of central nervous system (CNS) viral infection to further understand the role and regulation of CD4+ T cell responses in immunopathology. In this model, intracranial (i.c.) infection of immunocompetent mice with lymphocytic choriomeningitis virus (LCMV) results in fatal meningitis mediated by CD8+ T cells by day 8 post-infection. I.c. LCMV infection of mice deficient in CD8+ T cells, either by deficiency in β₂ microglobulin (β₂m^-/-) or in vivo depletion, results in less severe meningitis and lower mortality rate. CD8+ T cell-deficient mice also develop severe anorexia and weight loss; these symptoms, as well as meningitis, are mediated by anti-viral CD4+ T cell responses and are not affected by viral titer. Thus, this mouse model allows us to directly examine: (i) factors that influence immunopathologic CD4+ T cell responses to viral infection; and (ii) mechanism(s) downstream of CD4+ T cell responses that control immunopathologic disease. Identification of mechanism(s) that control the magnitude and downstream sequelae of the viral-specific CD4+ T cell response will enhance our understanding of the regulation of and our ability to treat immunopathologic disease.

This dissertation investigated three main hypotheses: (i) androgens and NKT cells independently regulate the quantity and quality of viral-specific CD4+ T cell responses; (ii) type I interferon signaling controls the activation of NKT cells during viral infection; and (iii) type II interferon (IFN-γ) signaling controls recruitment and activation of antigen-presenting cells (APCs) but not viral-specific CD4+ T cell responses. Our work shows that CD4+ T cell production of IFN-γ can regulate immunopathologic disease via signaling to macrophage-lineage cells. Further, such IFN-γ signaling controls chemokine production and antigen-presenting cell (APC) activation within and recruitment to the CNS. However, IFN-γ does not control the magnitude of viral-specific CD4+ T cell responses. Instead, we found that the actions of sex hormones and the action of NKT cells independently regulate the magnitude of viral-specific CD4+ T cell responses. Finally, we found that NKT cells required type I interferon signaling for activation and likely control viral-specific CD4+ T cell responses through their effects on dendritic cell co-stimulatory molecule expression. These findings have significant implications for our understanding of sex differences in susceptibility to autoimmunity and the development of therapies for disease-associated anorexia and neuroinflammatory and immune-mediated diseases.