NKT cells support B lymphocyte functions independently of expression of the adapter SAP. (106.45)

Abstract

Abstract Patients with X-linked lymphoproliferative disease (XLP) who lack functional SLAM-associated protein (SAP) have both impaired NKT cells development and progressive agammaglobulinemia. 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. NKT cell-dependent B cell responses were absent in SAP-/-.B6 mice that lack NKT cells. However, the small number of 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 post-development in SAPfl/fl.tgCreERT2.B6 mice. These animals have normal numbers of SAP-deficient NKT cells, which efficiently support early antibody responses in the presence of αGalCer. NKT cell help during late responses does not depend upon the NKT cell intrinsic expression of SAP, provided that the conventional T cells express the adapter, as judged by adoptive transfer experiments. Thus, SAP-dependent signaling is only critical for those NKT-helper functions that act via CD4+ T cells. We conclude that SAP expression in NKT cells is dispensable for their ability to help antibody production, which suggests that residual NKT cells might contribute to the variable dysgammaglobulinemia in XLP patients.