title: SAP expression in invariant NKT cells is required for cognate help to support B-cell responses.
abstract: 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 and NK cells. 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 NKT cells, 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 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.
authors.affiliation: Division of Immunology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA. cdetre@bidmc.harvard.edu
authors.forename: Cynthia
authors.initials: C
authors.lastname: Detre
authors.forename: Marton
authors.initials: M
authors.lastname: Keszei
authors.forename: Natividad
authors.initials: N
authors.lastname: Garrido-Mesa
authors.forename: Katalin
authors.initials: K
authors.lastname: Kis-Toth
authors.forename: Wilson
authors.initials: W
authors.lastname: Castro
authors.forename: Amma F
authors.initials: AF
authors.lastname: Agyemang
authors.forename: Natacha
authors.initials: N
authors.lastname: Veerapen
authors.forename: Gurdyal S
authors.initials: GS
authors.lastname: Besra
authors.forename: Michael C
authors.initials: MC
authors.lastname: Carroll
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
authors.forename: Ninghai
authors.initials: N
authors.lastname: Wang
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Leadbetter
authors.forename: Cox
authors.initials: C
authors.lastname: Terhorst
mesh_terms: D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology*; D002450:Cell Communication / Q000187:drug effects / Q000276:immunology; D005260:Female; D005699:Galactosylceramides / Q000378:metabolism / Q000494:pharmacology; D015870:Gene Expression / Q000276:immunology; D018858:Germinal Center / Q000276:immunology; D006241:Haptens / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000276:immunology*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D013629:Tamoxifen / Q000494:pharmacology
chemical_list: D018931:Antineoplastic Agents, Hormonal; D005699:Galactosylceramides; D006241:Haptens; D047908:Intracellular Signaling Peptides and Proteins; C499569:Sh2d1a protein, mouse; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; C493154:alpha-galactosylceramide; D013629:Tamoxifen