TY - JOUR
T1 - A role for DRAK2 in the germinal center reaction and the antibody response
AU - Al-Qahtani, Ahmed
AU - Xu, Zhenming
AU - Zan, Hong
AU - Walsh, Craig
AU - Casali, Paolo
N1 - Funding Information:
Correspondence: P. Casali, Center for Immunology, University of California, 3028 Hewitt Hall, Irvine, CA 92697-4120, USA. Tel: (949) 824 9648. Fax: (949) 824 2305. E-mail: [email protected] †This work was supported by N.I.H. grants AI 45011 and AI 60573 to P.C., and AI 63419 to C.M.W.
PY - 2008/7
Y1 - 2008/7
N2 - 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.
AB - 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.
KW - Antibodies
KW - B cells
KW - Molecular biology
KW - Spleen and germinal centers
KW - Transgenic/knockout mice
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U2 - 10.1080/08916930802170633
DO - 10.1080/08916930802170633
M3 - Article
C2 - 18568639
AN - SCOPUS:45949102115
SN - 0891-6934
VL - 41
SP - 341
EP - 352
JO - Autoimmunity
JF - Autoimmunity
IS - 5
ER -