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

SummaryHumans 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.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (396 K)Download as PowerPoint slideHighlights► Ly108 inhibits long-term T cell:B cell conjugates and germinal centers in the absence of SAP ► Ly108 inhibition is dependent on SHP-1 and immunotyrosine switch motifs (ITSM) ► In the absence of SAP, Ly108 recruits SHP-1 to the T cell:B cell synapse ► Absence of Ly108 expression rescues NKT cell development in Slamf6−/−Sh2d1a−/− mice