The receptor Ly108 functions as a SAP adaptor-dependent on-off switch for T cell help to B cells and NKT cell development

Immunity. 2012 Jun 29;36(6):986-1002. doi: 10.1016/j.immuni.2012.05.016. Epub 2012 Jun 7.

Abstract

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.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs
  • Animals
  • Antigens, Ly / genetics
  • Antigens, Ly / physiology*
  • B-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / immunology*
  • Germinal Center / immunology
  • Immunologic Deficiency Syndromes / genetics
  • Immunologic Deficiency Syndromes / immunology
  • Immunological Synapses / immunology
  • Inositol Polyphosphate 5-Phosphatases
  • Intracellular Signaling Peptides and Proteins / deficiency
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / physiology
  • Lymphocyte Cooperation / physiology*
  • Lymphopoiesis / physiology*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Natural Killer T-Cells / cytology*
  • Phosphoric Monoester Hydrolases / physiology
  • Phosphorylation
  • Phosphotyrosine / physiology
  • Protein Processing, Post-Translational
  • Signaling Lymphocytic Activation Molecule Associated Protein

Substances

  • Antigens, Ly
  • Intracellular Signaling Peptides and Proteins
  • Ly108 protein, mouse
  • Sh2d1a protein, mouse
  • Signaling Lymphocytic Activation Molecule Associated Protein
  • Phosphotyrosine
  • Phosphoric Monoester Hydrolases
  • Inositol Polyphosphate 5-Phosphatases