TY - JOUR
T1 - The Receptor Ly108 Functions as a SAP Adaptor-Dependent On-Off Switch for T Cell Help to B Cells and NKT Cell Development
AU - Kageyama, Robin
AU - Cannons, Jennifer L.
AU - Zhao, Fang
AU - Yusuf, Isharat
AU - Lao, Christopher
AU - Locci, Michela
AU - Schwartzberg, Pamela L.
AU - Crotty, Shane
N1 - Funding Information:
We thank I. Engel and M. Kronenberg for technical advice. Slamf6 mice were obtained through the NIH KOMP Repository program. This work was supported by NIH grants and LIAI institutional funds (S.C.) and the NIH NHGRI intramural program (P.L.S., J.L.C., F.Z.). F.Z. is a Scholar in the NIH-Oxford-Cambridge Scholars in Biomedical Research program.
PY - 2012/6/29
Y1 - 2012/6/29
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84862988085&partnerID=8YFLogxK
U2 - 10.1016/j.immuni.2012.05.016
DO - 10.1016/j.immuni.2012.05.016
M3 - Article
C2 - 22683125
AN - SCOPUS:84862988085
SN - 1074-7613
VL - 36
SP - 986
EP - 1002
JO - Immunity
JF - Immunity
IS - 6
ER -