The fate of B cells in HIV infection - shifting the balance from plasma cell towards regulatory B cell (Breg) differentiation (LYM6P.776)

Abstract

Abstract Certain regulatory lymphocyte populations suppress T cell expansion in a granzyme B (GrB)-dependent manner. Recently, we found that human B cells also contribute to immune regulation by interleukin (IL-)21-dependent expression of GrB. GrB-expressing Bregs are induced by incompletely activated CD4+ T cells, which express high levels of IL-21, but only low CD40 ligand. In contrast, fully activated CD4+ T cells strongly induce plasma cell differentiation. Here we demonstrate that up to 60% of B cells from HIV-infected patients with high viremia exhibit a regulatory (Breg) phenotype with expression of GrB and potent suppression of T cell proliferation by GrB-dependent degradation of the T cell receptor zeta-chain (TCR-zeta). These results are supported by additional findings showing that T cells in HIV-infected individuals produce high levels of IL-21, while expressing only low levels of CD40L and TCR-zeta. Importantly, soluble CD40L multimers can restore the differentiation of Bregs derived from HIV-infected individuals into plasma cells. Our results suggest that incompletely activated CD4+ T cells in HIV patients lead to a misrouting of B cell differentiation into Bregs at the cost of fully functional plasma cells. Apart from a disturbed humoral immune response these B cells may further aggravate the immune status of HIV patients. The use of CD40L multimers may disrupt the defective B cell-T cell interactions and may prove beneficial for future HIV vaccination approaches.