A role for Drak2 in the germinal center reaction and the antibody response

Abstract

DAP‐related apoptotic kinase‐2 (Drak2), a DAP family member, is highly expressed in B and T lymphocytes in the human and the mouse. To determine whether Drak2 plays a role in B cell activation and differentiation, we analyzed germinal center (GC) development in drak2−/− mice immunized with the T‐dependent conjugated hapten NP‐CGG. In drak2−/− mice, spleen GCs were normal in size and morphology, but their number was reduced by three to five‐fold as compared to wild type littermates. This was not due to a defect in B cell proliferation, as BrdU uptake in vivo and CFSE staining in vitro of B cells was comparable in Drak2‐deficient and wild type B cells. Nevertheless, the proportion of apoptotic GC B and T cells in drak2−/− mice was significantly higher than that in wild type littermates as shown by7‐AAD and TUNEL staining experiments. As a result, the generation of high affinity IgG antibodies was impaired in drak2−/− mice. Enforced expression of bcl‐xl in T cells of these mice increased the number of the GCs and rescued the high affinity IgG response to NP‐CGG. This was consistent with the findings that the somatic hypermutation and class switch DNA recombination machineries were inherently normal in drak2−/− mice. Thus, our findings suggest a novel role of Drak2 in regulating the GC reaction and the response to TD antigens.This work is supported by NIH grants AI 45011, AI 60573 and AR 40908.