Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency

Snow, Andrew L.; Marsh, Rebecca; Krummey, Scott M.; Roehrs, Philip; Young, Lisa R.; Zhang, Kejian; Hoff, Jack van; Dhar, Deepali; Nichols, Kim E.; Filipovich, Alexandra H.; Su, Helen C.; Bleesing, Jack J.; Lenardo, Michael J.

doi:10.1172/jci39518

Cited by 106 publications

(184 citation statements)

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“…Moreover, two independent reports have shown that SAP has a function in activation-induced cell death of T cells. 5,15 Mutation or deletion of the SAP gene causes the XLP immunodeficiency syndrome. [16][17][18] In immunocompetent individuals, primary infection with EBV can lead to a self-limiting lymphoproliferatve disease, infectious mononucleosis.…”

Section: Discussionmentioning

confidence: 99%

p53 contributes to T cell homeostasis through the induction of pro-apoptotic SAP

et al. 2012

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Section: Discussionmentioning

confidence: 99%

p53 contributes to T cell homeostasis through the induction of pro-apoptotic SAP

et al. 2012

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“…To test RICD sensitivity, activated human T cells were treated in triplicate with anti-CD3ε mAb OKT3 (1-500 ng/ml; Ortho Biotech), as previously described (4). For some assays, cells were pretreated for 30 min with 0.2 mM LCK inhibitor I or SU6656 (EMD Millipore) versus DMSO solvent control.…”

Section: Apoptosis Assays and Flow Cytometrymentioning

confidence: 99%

“…In activated human T cells, our previous work suggested that SAP dislodges the phosphatase SHP-1 from NTB-A shortly after restimulation, removing a negative regulatory checkpoint for TCR signaling. However, reducing SHP-1 expression in the T cells of XLP patients did not fully rescue RICD, suggesting SAP also transmits a positive signal through NTB-A that potentiates RICD (4).…”

mentioning

confidence: 94%

“…Recently, the clinical significance of this process was underscored in patients with X-linked lymphoproliferative disease (XLP) (4)(5)(6). Most cases of XLP are linked to mutations or deletions in SH2D1A, which encodes the signaling lymphocyte activation molecule (SLAM)-associated protein (SAP) (7).…”

mentioning

confidence: 99%

“…We previously found that RICD was specifically impaired in the T cells of XLP patients, suggesting this apoptosis defect contributes to excessive accumulation of activated T cells. Both SAP and the SLAM family receptor NK, T, and B cell Ag (NTB-A) are required for optimal RICD of normal human T cells (4).…”

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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.

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Reporting of Clinical Genome Sequencing Results

2018

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High-throughput sequencing and high-performance computing technologies have become powerful tools in clinical genetic diagnosis of hereditary disorders and genetic screening of healthy individuals to provide information for the diagnosis, treatment, and prevention of diseases or impairment and assessment of health. For patients with undiagnosed disorders, including many rare disorders, the whole-genome sequencing (WGS) test may end the diagnostic odyssey, ultimately guiding clinical care for them and their families. A clinical WGS test relies on high-quality genome-sequencing data as well as sophisticated data-interpretation approaches. Results are returned to the ordering physician in a concise report featuring an overall test result and in-depth phenotype-driven interpretation of the known or plausible genetic explanation of test indications. Patients have the option to decide whether the report should include secondary and incidental findings. Protocols and templates for reporting clinical WGS results and supplementary information are described in this article. © 2018 by John Wiley & Sons, Inc.

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Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency

Cited by 106 publications

References 45 publications

p53 contributes to T cell homeostasis through the induction of pro-apoptotic SAP

p53 contributes to T cell homeostasis through the induction of pro-apoptotic SAP

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

Reporting of Clinical Genome Sequencing Results

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