Functional heterogeneity and helper roles of CD4+ T cells in antiviral immunity

CD4+ T cells are critical for the control of virus infections, memory cell formation and immune surveillance. Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus are two gamma-herpesviruses identified in humans and are strongly associated with the development of malignancies. Murine gamma-herpesvirus (MHV-68) is a naturally occurring rodent pathogen, representing a unique experimental model for dissecting gamma-herpesvirus infection and the immune response. Vaccinia virus (VACV), a smallpox vaccination, has been used as a vector to study biological functions of foreign genes. In this project, we focused on studying the functional heterogeneity and helper roles of CD4+ T cells in antiviral immunity, which mainly consists of three topics. (i) We studied functional heterogeneity of the MHV-68 specific CD4+ T cells by using MHV-68 gp15067-83 epitope-specific TCR transgenic mice. The CD4+ T cell response could protect against virus infection independent of CD8+ T cells and B cells. The response in vivo was markedly heterogeneous, divisible by differential Ly6C expression. Ly6C may be used as a surface marker to distinguish functionally distinct CD4+ T cells during persistent virus infection. (ii) We studied the role of CD4+ T cell help in immune surveillance against MHV-68 by exploring a population of suppressive IL-10 producing CD8+ T cells that were induced in the absence of CD4+ T cells. We characterized the phenotype and function of an IL-10 producing CD8+ T cell population and demonstrated that the population belongs to a subset of CD8+ T regulatory cells. (iii) We studied the effect of CD4+ T cell help on primary CD8+ T cell response to acute viral infection in MHCII -/- mice infected with VACV. Our results indicate that route of infection and viral dose are two determinants for CD4 help dependence, and intranasal infection induces more potent effector CD8+ T cells than intraperitoneal infection. This study provides a clearer picture of how CD4+ T cells play multiple roles in orchestrating and mediating the immune responses against viral infections. Elucidating differentiation and function of CD4 + T cells is critical for understanding the pathogenesis, generation of effective immunotherapy and development of vaccine candidates.