A role for DRAK2 in the germinal center reaction and the antibody response.
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.
Center for Immunology, University of California, Irvine, CA, USA.
Ahmed
A
Al-Qahtani
Zhenming
Z
Xu
Hong
H
Zan
Craig M
CM
Walsh
Paolo
P
Casali
D000818:Animals; D000917:Antibody Formation; D000918:Antibody Specificity; D017209:Apoptosis; D001402:B-Lymphocytes / Q000276:immunology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D018858:Germinal Center / Q000276:immunology*; D017578:Immunoglobulin Class Switching; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D009596:Nitrophenols / Q000276:immunology; D010648:Phenylacetates; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000276:immunology*; D027041:Somatic Hypermutation, Immunoglobulin; D013154:Spleen / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D051020:bcl-X Protein / Q000276:immunology
C494812:Bcl2l1 protein, mouse; D007074:Immunoglobulin G; D009596:Nitrophenols; D010648:Phenylacetates; D051020:bcl-X Protein; C026242:4-hydroxy-5-nitrophenyl acetic acid; C495197:Drak2 protein, mouse; D017346:Protein Serine-Threonine Kinases