Manipulation of antibody responses by a retrovirus - Abstract Following exposure to antigens, naïve B cells differentiate by going through germinal center reaction into plasma cells or memory B cells. Plasma cells secrete antigen-specific antibodies which aid in the clearance of invading pathogens by direct neutralization, by activating the complement cascade or by interacting with other immune cells by binding to Fc receptors. Long lived memory B cells can be reactivated to differentiate into plasma cells following secondary infection. Together, memory B cells and long-lived plasma cells form the basis for life-long B cell-mediated protection against various infections. To evade host protective immunity all successful pathogens have evolved numerous mechanism to directly or indirectly manipulate B cells. Pathogens could manipulate B cells by using them as a reservoir, by interfering with B cell maturation and by modulating B cell survival. Mouse mammary tumor virus (MMTV) is an exogenous retrovirus which persist indefinitely in mice of susceptible strains. B cells represent the primary and indispensable target for this virus and yet persistently infected mice do not make significant titers of virus-neutralizing Abs. Unlike mice from MMTV-susceptible mice I/LnJ mice even though become virus-infected produced potent virus-neutralizing Ab responses leading to the virus elimination. Using a positional cloning approach, we discovered the negative immune regulator of the major histocompatibility class II (MHCII) peptide presentation, DO is dysfunctional in mice from the I/LnJ strain and its dysfunction is a sole reason why these mice generate virus-neutralizing Ab responses. DO is a non-classical Major Histocompatibility Class II (MHCII)-like molecule which has evolved as a negative regulator of yet another MHCII-like molecule, DM. DM catalyzes peptide loading of MHCII on antigen presenting cells (APCs) for presentation to CD4 T cells. In the absence of DO there is a significant increase of high-affinity peptides presented by MHCII as DM is uninhibited. Whereas naïve B cells express high levels of DO, DO is downregulated during generation of Ab responses to allow for presentation of high affinity peptides and entering the germinal center reactions. We hypothesis that non-lytic viruses that infect B cells prevent downregulation of DO in germinal center B cells to avoid presentation of high affinity virus-specific peptides. The studies described in this basic science proposal will determine whether a B cell infecting retrovirus, such as MMTV impedes the mechanisms controlling DO levels in germinal center B cells to prevent the development of isotype switched, virus-specific Ab responses.
