TY - JOUR
T1 - SAP facilitates recruitment and activation of LCK at NTB-A receptors during restimulation-induced cell death
AU - Katz, Gil
AU - Krummey, Scott M.
AU - Larsen, Sasha E.
AU - Stinson, Jeffrey R.
AU - Snow, Andrew L.
N1 - Copyright:
Copyright 2014 Elsevier B.V., All rights reserved.
PY - 2014/5/1
Y1 - 2014/5/1
N2 - Upon TCR restimulation, activated, cycling T cells can undergo a self-regulatory form of apoptosis known as restimulation-induced cell death (RICD). We previously demonstrated that RICD is impaired in T cells from patients with X-linked lymphoproliferative disease, which lack SLAM-associated protein (SAP) expression. Both SAP and the specific SLAM receptor NK, T, and B cell Ag (NTB-A) are required for RICD, but the mechanism by which these molecules promote a strong, proapoptotic signal through the TCR remains unclear. In this article, we show that the Src-family kinase LCK, but not FYN, associates with NTB-A in activated human T cells. This association increased after TCR restimulation in a SAP-dependent manner, requiring both immunoreceptor tyrosine-based switch motifs in the NTB-A cytoplasmic tail. Both NTB-A-associated LCK phosphorylation and kinase activity were enhanced in restimulated T cells, amplifying proximal TCR signaling. In contrast, TCR-induced LCK association with NTB-A, as well as phosphorylation and kinase activity, was reduced in T cells from patients with X-linked lymphoproliferative disease or normal T cells transfected with SAP-specific small interfering RNA, consistent with RICD resistance. Collectively, our data reveal how SAP nucleates a previously unknown signaling complex involving NTB-A and LCK to potentiate RICD of activated human T cells. The Journal of Immunology, 2014, 192: 4202-4209.
AB - Upon TCR restimulation, activated, cycling T cells can undergo a self-regulatory form of apoptosis known as restimulation-induced cell death (RICD). We previously demonstrated that RICD is impaired in T cells from patients with X-linked lymphoproliferative disease, which lack SLAM-associated protein (SAP) expression. Both SAP and the specific SLAM receptor NK, T, and B cell Ag (NTB-A) are required for RICD, but the mechanism by which these molecules promote a strong, proapoptotic signal through the TCR remains unclear. In this article, we show that the Src-family kinase LCK, but not FYN, associates with NTB-A in activated human T cells. This association increased after TCR restimulation in a SAP-dependent manner, requiring both immunoreceptor tyrosine-based switch motifs in the NTB-A cytoplasmic tail. Both NTB-A-associated LCK phosphorylation and kinase activity were enhanced in restimulated T cells, amplifying proximal TCR signaling. In contrast, TCR-induced LCK association with NTB-A, as well as phosphorylation and kinase activity, was reduced in T cells from patients with X-linked lymphoproliferative disease or normal T cells transfected with SAP-specific small interfering RNA, consistent with RICD resistance. Collectively, our data reveal how SAP nucleates a previously unknown signaling complex involving NTB-A and LCK to potentiate RICD of activated human T cells. The Journal of Immunology, 2014, 192: 4202-4209.
UR - http://www.scopus.com/inward/record.url?scp=84899506893&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84899506893&partnerID=8YFLogxK
U2 - 10.4049/jimmunol.1303070
DO - 10.4049/jimmunol.1303070
M3 - Article
C2 - 24688028
AN - SCOPUS:84899506893
SN - 0022-1767
VL - 192
SP - 4202
EP - 4209
JO - Journal of Immunology
JF - Journal of Immunology
IS - 9
ER -