Al-Qahtani Ahmed, Xu Zhenming, Zan Hong, Walsh Craig M, Casali Paolo
Center for Immunology, University of California, Irvine, CA, USA.
Autoimmunity. 2008 Aug;41(5):341-52. doi: 10.1080/08916930802170633.
DAP-related apoptotic kinase-2 (DRAK2), a death-associated protein kinase 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 centers (GCs) and the specific antibody response to NP in drak2-/- mice immunized with the thymus-dependent (TD) conjugated hapten NP16-CGG. In drak2-/- mice, spleen GCs were normal in size and morphology, but their number was reduced by as much as 5-fold, as compared to their wild-type littermates. This was not due to a defect in B-cell proliferation, as the BrdU uptake was comparable in DRAK2-deficient and wild-type B cells. Rather, the proportion of apoptotic GC B and T cells in drak2-/- mice was significantly higher than that in wild-type control mice, as shown by 7-AAD and terminal deoxynucleotide transferase dUTP nick end labeling (TUNEL) staining. In drak2-/- mice, the generation high affinity IgG antibodies was impaired in spite of the seemingly normal somatic hypermutation and class switch DNA recombination machineries in drak2-/- B cells. In NP16-CGG-immunized drak2-/- mice, T-cell-intrinsic Bcl-xL transgene expression increased the number of GCs and rescued the high affinity IgG response to NP. These findings suggest a novel role for DRAK2 in regulating the GC reaction and the response to TD antigens, perhaps through increased survival of T cells and enhanced B-cell positive selection. They also suggest that DRAK2-deficiency is not involved in regulating intrinsic B-cell apoptosis.
死亡相关凋亡激酶2（DRAK2）是死亡相关蛋白激酶家族成员，在人和小鼠的B细胞和T淋巴细胞中高表达。为了确定DRAK2是否在B细胞活化和分化中发挥作用，我们分析了用胸腺依赖性（TD）偶联半抗原NP16-CGG免疫的drak2-/-小鼠的生发中心（GCs）以及对NP的特异性抗体反应。在drak2-/-小鼠中，脾脏GCs的大小和形态正常，但与野生型同窝小鼠相比，其数量减少了多达5倍。这并非由于B细胞增殖缺陷，因为在DRAK2缺陷型和野生型B细胞中BrdU摄取相当。相反，如7-AAD和末端脱氧核苷酸转移酶dUTP缺口末端标记（TUNEL）染色所示，drak2-/-小鼠中凋亡的GC B细胞和T细胞比例明显高于野生型对照小鼠。在drak2-/-小鼠中，尽管drak2-/- B细胞中看似正常的体细胞超突变和类别转换DNA重组机制，但高亲和力IgG抗体的产生受损。在NP16-CGG免疫的drak2-/-小鼠中，T细胞内在的Bcl-xL转基因表达增加了GCs的数量，并挽救了对NP的高亲和力IgG反应。这些发现表明DRAK2在调节GC反应和对TD抗原的反应中具有新作用，可能是通过增加T细胞存活和增强B细胞阳性选择。它们还表明DRAK2缺陷不参与调节内在B细胞凋亡。
