The Receptor Ly108 Functions as a SAP Adaptor-Dependent On-Off Switch for T Cell Help to B Cells and NKT Cell Development

Robin Kageyama, Jennifer L. Cannons, Fang Zhao, Isharat Yusuf, Christopher Lao, Michela Locci, Pamela L. Schwartzberg, Shane Crotty

Research output: Contribution to journalArticlepeer-review

119 Scopus citations

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.

Original languageEnglish
Pages (from-to)986-1002
Number of pages17
JournalImmunity
Volume36
Issue number6
DOIs
StatePublished - Jun 29 2012

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