The receptor Ly108 functions as a SAP adaptor-dependent on-off switch for T cell help to B cells and NKT cell development.
Humans and mice deficient in the adaptor protein SAP (Sh2d1a) have a major defect in humoral immunity, resulting from a lack of T cell help for B cells. The role of SAP in this process is incompletely understood. We found that deletion of receptor Ly108 (Slamf6) in CD4(+) T cells reversed the Sh2d1a(-/-) phenotype, eliminating the SAP requirement for germinal centers. This potent negative signaling by Ly108 required immunotyrosine switch motifs (ITSMs) and SHP-1 recruitment, resulting in high amounts of SHP-1 at the T cell:B cell synapse, limiting T cell:B cell adhesion. Ly108-negative signaling was important not only in CD4(+) T cells; we found that NKT cell differentiation was substantially restored in Slamf6(-/-)Sh2d1a(-/-) mice. The ability of SAP to regulate both positive and negative signals in T cells can explain the severity of SAP deficiency and highlights the importance of SAP and SHP-1 competition for Ly108 ITSM binding as a rheostat for the magnitude of T cell help to B cells.
Division of Vaccine Discovery, La Jolla Institute for Allergy & Immunology, La Jolla, CA 92037, USA.
Robin
R
Kageyama
Jennifer L
JL
Cannons
Fang
F
Zhao
Isharat
I
Yusuf
Christopher
C
Lao
Michela
M
Locci
Pamela L
PL
Schwartzberg
Shane
S
Crotty
D020816:Amino Acid Motifs; D000818:Animals; D000950:Antigens, Ly / Q000235:genetics / Q000502:physiology*; D001402:B-Lymphocytes / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018858:Germinal Center / Q000276:immunology; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology; D054992:Immunological Synapses / Q000276:immunology; D000072181:Inositol Polyphosphate 5-Phosphatases; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D008211:Lymphocyte Cooperation / Q000502:physiology*; D038041:Lymphopoiesis / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055611:Natural Killer T-Cells / Q000166:cytology*; D010744:Phosphoric Monoester Hydrolases / Q000502:physiology; D010766:Phosphorylation; D019000:Phosphotyrosine / Q000502:physiology; D011499:Protein Processing, Post-Translational; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; D000071176:Signaling Lymphocytic Activation Molecule Family
D000950:Antigens, Ly; D000072181:Inositol Polyphosphate 5-Phosphatases; D047908:Intracellular Signaling Peptides and Proteins; D010744:Phosphoric Monoester Hydrolases; D019000:Phosphotyrosine; D000071179:Signaling Lymphocytic Activation Molecule Associated Protein; C499569:Sh2d1a protein, mouse; C000604063:Slamf6 protein, mouse; D000071176:Signaling Lymphocytic Activation Molecule Family