Differential expression of the adaptor protein HSH2 inversely affects class-switched antibody production and antibody-secreting cell generation (LYM7P.617)

Abstract

Abstract Hematopoietic Src homology 2 domain (HSH2) is a conserved adapter protein that exhibits differential expression in peripheral B cell subsets. The reason for this differential expression is not clear. Therefore, to assess the impact of differential HSH2 expression on B cell function, we employed mouse models expressing either high or low levels of HSH2. Following immunization with either TI or TD antigens, we observed a marked alteration in class-switched antibody (Ab) production that inversely correlated with HSH2 levels, with the greatest effect being on IgG3. Furthermore, in vitro and in vivo we observed a decreased number of class-switched Ab-secreting cells (ASC) in the HSH2hi mice and an increase in ASCs in the HSH2lo mice. Overall, these data show that HSH2 levels inversely correlate with class-switched Ab production likely through alteration of class-switched B cell differentiation into ASCs. This novel function of HSH2 reveals its importance in B cell biology. Because HSH2 acts as a potential rheostat able to modulate the production of class-switched B cells depending on its expression level, this highlights the potential for HSH2 to play an important role in disease processes involving class-switched Abs and for vaccine development where generation of class-switched high-affinity Abs is the goal.