Control of T Lymphocyte Signaling by Ly108, a Signaling Lymphocytic Activation Molecule Family Receptor Implicated in Autoimmunity

Zhong, Ming-Chao; Veillette, André

doi:10.1074/jbc.m800209200

Cited by 59 publications

(75 citation statements)

References 37 publications

(34 reference statements)

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“…FYN is considered the key Src-family kinase required for SLAM-R signaling, based on its SAP-dependent association with several other SLAM-Rs (13)(14)(15)(16)(17)(18)(19)(20). Although LCK was previously implicated in phosphorylation of both SLAM and CD84 (17,24), no direct association between LCK and a SLAM-R had been detected to date.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies either relied on overexpression constructs for biochemical analysis of NTB-A signaling (19) or focused on thymocytes, NK cells, or NK cell lines (13)(14)(15)(16)(17)(18)(19)(20). In the latter case, it is possible that cell type-based differences in the expression of FYN, LCK, SAP, or the SLAM family receptor examined could account for differences in the associations detected.…”

Section: Discussionmentioning

confidence: 99%

“…Two Srcfamily kinases are primarily involved in initiating TCR signaling: LCK and FYN (12). FYN is the major Src-family kinase shown to mediate signal transduction of SLAM-Rs (including NTB-A) in thymocytes and NK cells (13)(14)(15)(16)(17)(18)(19)(20). To examine the role of both FYN and LCK in RICD, we first used highly selective inhibitors for FYN (SU6656) (21) or LCK [LCK inhibitor I (LCKi)] (22).…”

Section: Ricd Of Human T Cells Is Not Dependent On Fynmentioning

confidence: 99%

“…The cytoplasmic tail of NTB-A contains three tyrosinebased motifs that regulate signal transduction: Y273 is part of a putative ITIM, whereas Y284 and Y308 are each part of an ITSM (8). Because SAP binding to NTB-A is reported to be dependent on phosphorylation of one or more of these tyrosines (19,20), we next asked which tyrosines in the NTB-A cytoplasmic tail are important for increased SAP-dependent LCK recruitment and phosphorylation during restimulation. To address this question, we stably expressed wild-type (WT) NTB-A or single tyrosine-tophenylalanine (Y→F) NTB-A cytoplasmic tail mutants (Y273F, Y284F, or Y308F) in the NTB-A-negative T cell line PEER (10).…”

Section: Increased Recruitment and Y394 Phosphorylation Of Ntb-a-assomentioning

confidence: 99%

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SAP Facilitates Recruitment and Activation of LCK at NTB-A Receptors during Restimulation-Induced Cell Death

Katz

Krummey

Larsen

et al. 2014

The Journal of Immunology

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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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Ricd Of Human T Cells Is Not Dependent On Fynmentioning

confidence: 99%

Section: Increased Recruitment and Y394 Phosphorylation Of Ntb-a-assomentioning

confidence: 99%

See 2 more Smart Citations

SAP Facilitates Recruitment and Activation of LCK at NTB-A Receptors during Restimulation-Induced Cell Death

Katz

Krummey

Larsen

et al. 2014

The Journal of Immunology

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show abstract

“…Analysis of expression of CS1 isoforms indicates differential expression of CS1-L and CS1-S isoform in SLE PBMCs, reminiscent of Ly108 expression in lupus-prone mice [59,60]. The CS1-S isoform does not contain two ITSMs and does not mediate signalling [38].…”

Section: Discussionmentioning

confidence: 99%

Altered expression of signalling lymphocyte activation molecule (SLAM) family receptors CS1 (CD319) and 2B4 (CD244) in patients with systemic lupus erythematosus

Kim¹,

Mathew²,

Patel

et al. 2010

Clinical and Experimental Immunology

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T/B‐cell interactions are more transient in response to weak stimuli in SLE‐prone mice

et al. 2014

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Changes in immune function during the course of systemic lupus erythematosus (SLE) are well characterized. Class-switched antinuclear antibodies are the hallmark of SLE, and T/B- cell interactions are thus critical. However, changes in immune function contributing to disease susceptibility are unknown. Here, we have analyzed primary T and B cells from a mouse model of SLE prior to the onset of disease. To allow cognate T-cell activation with low affinity, we have developed a lower potency peptide ligand for the OTII T-cell receptor. T and B-cell couples formed less frequently and retained their polarity less efficiently preferentially in response to low affinity stimulation in SLE-prone mice. This matched decreased recruitment of actin and Vav1 and an enhanced PKCΘ recruitment to the cellular interface in T cells. The induction of the germinal center B-cell marker GL7 was increased in T/B cell couples from SLE-prone mice when the T-cell numbers were limited. However, the overall gene expression changes were marginal. Taken together, the enhanced cell couple transience may allow a more efficient sampling of a large number of T/B cell couples, preferentially in response to limiting stimuli, therefore enhancing the immune reactivity in the development of SLE.

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Control of T Lymphocyte Signaling by Ly108, a Signaling Lymphocytic Activation Molecule Family Receptor Implicated in Autoimmunity

Cited by 59 publications

References 37 publications

SAP Facilitates Recruitment and Activation of LCK at NTB-A Receptors during Restimulation-Induced Cell Death

SAP Facilitates Recruitment and Activation of LCK at NTB-A Receptors during Restimulation-Induced Cell Death

Altered expression of signalling lymphocyte activation molecule (SLAM) family receptors CS1 (CD319) and 2B4 (CD244) in patients with systemic lupus erythematosus

T/B‐cell interactions are more transient in response to weak stimuli in SLE‐prone mice

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