TY - JOUR
T1 - SAP expression in invariant NKT cells is required for cognate help to support B-cell responses
AU - Detre, Cynthia
AU - Keszei, Marton
AU - Garrido-Mesa, Natividad
AU - Kis-Toth, Katalin
AU - Castro, Wilson
AU - Agyemang, Amma F.
AU - Veerapen, Natacha
AU - Besra, Gurdyal S.
AU - Carroll, Michael C.
AU - Tsokos, George C.
AU - Wang, Ninghai
AU - Leadbetter, Elizabeth A.
AU - Terhorst, Cox
PY - 2012/7/5
Y1 - 2012/7/5
N2 - One of the manifestations of X-linked lymphoproliferative disease (XLP) is progressive agammaglobulinemia, caused by the absence of a functional signaling lymphocyte activation molecule (SLAM) - associated protein (SAP) in T, invariant natural killer T (NKT) cells andNKcells. Here we report that α-galactosylceramide (αGalCer) activated NKT cells positively regulate antibody responses to haptenated protein antigens at multiple checkpoints, including germinal center formation and affinity maturation. Whereas NKT cell-dependent B cell responses were absent in SAP-/-.B6 mice that completely lack NKTcells, the smallnumberof SAP-deficient NKT cells in SAP-/-.BALB/c mice adjuvated antibody production, but not the germinal center reaction. To test the hypothesis that SAP-deficient NKT cells can facilitate humoral immunity, SAP was deleted after development in SAP fl/fl.tgCreERT2.B6 mice. We find that NKT cell intrinsic expression of SAP is dispensable for noncognate helper functions, but is critical for providing cognate help to antigen-specific B cells. These results demonstrate that SLAM-family receptor-regulated cell-cell interactions are not limited to T-B cell conjugates. We conclude that in the absence of SAP, several routes of NKT cell- mediated antibody production are still accessible. The latter suggests that residual NKT cells in XLP patients might contribute to variations in dysgammaglobulinemia.
AB - One of the manifestations of X-linked lymphoproliferative disease (XLP) is progressive agammaglobulinemia, caused by the absence of a functional signaling lymphocyte activation molecule (SLAM) - associated protein (SAP) in T, invariant natural killer T (NKT) cells andNKcells. Here we report that α-galactosylceramide (αGalCer) activated NKT cells positively regulate antibody responses to haptenated protein antigens at multiple checkpoints, including germinal center formation and affinity maturation. Whereas NKT cell-dependent B cell responses were absent in SAP-/-.B6 mice that completely lack NKTcells, the smallnumberof SAP-deficient NKT cells in SAP-/-.BALB/c mice adjuvated antibody production, but not the germinal center reaction. To test the hypothesis that SAP-deficient NKT cells can facilitate humoral immunity, SAP was deleted after development in SAP fl/fl.tgCreERT2.B6 mice. We find that NKT cell intrinsic expression of SAP is dispensable for noncognate helper functions, but is critical for providing cognate help to antigen-specific B cells. These results demonstrate that SLAM-family receptor-regulated cell-cell interactions are not limited to T-B cell conjugates. We conclude that in the absence of SAP, several routes of NKT cell- mediated antibody production are still accessible. The latter suggests that residual NKT cells in XLP patients might contribute to variations in dysgammaglobulinemia.
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U2 - 10.1182/blood-2011-11-395913
DO - 10.1182/blood-2011-11-395913
M3 - Article
C2 - 22613797
AN - SCOPUS:84863562322
SN - 0006-4971
VL - 120
SP - 122
EP - 129
JO - Blood
JF - Blood
IS - 1
ER -