Neelam Panchal, United Kingdom

UCL GREAT ORMOND STREET INSTITUTE OF CHILD HEALTH MOLECULAR AND CELLULAR IMMUNOLOGY

Presenter of 1 Presentation

Meet the Expert T Cell Biology

ALLOSTERIC INHIBITION OF SHP2 RESCUES XLP PATIENT T CELL FUNCTION IN VITRO

Lecture Time
15:05 - 15:15
Room
Gold
Date
18.09.2019, Wednesday
Session Time
14:35 - 15:35
Presentation Topic
T Cell Biology

Abstract

Background and Aims

X-linked lymphoproliferative disease (XLP) is a severe primary immunodeficiency characterised by the loss of function of SLAM-associated protein (SAP) arising from mutations in the SH2D1A gene. SAP is an SH2 domain containing intracellular adaptor protein that relays T cell activatory signals from the T cell receptor (TCR) via ITSM motifs on SLAM family receptors. In the absence of SAP, alternative SH2 domain containing proteins such as SHP1, SHP2 and SHIP bind and induce T cell inhibitory signals leading to abnormal T cell responses. This results in debilitating clinical manifestations such as malignancy, haemophagocytic lymphohistiocytosis (HLH) and dysgammaglobulinaemia through impaired T and NK cell function. Current treatment involves HLH management, replacement immunoglobulin and haematopoietic stem cell transplantation (HSCT); however, HSCT can be associated with significant morbidity and mortality.

Methods

In this study we investigate the role of SHP2 in XLP patient T cell function in vitro using a small molecule allosteric inhibitor which stabilises an auto-inhibited conformation of SHP2.

Results

We show restoration of immunoglobulin and cytokine secretion through TFH: B cell co-culture assays, alongside rescue of cytotoxicity and re-stimulation induced cell death (RICD). Deep immunophenotyping and measurement of intracellular phosphorylation of signalling molecules (pSHP2, pERK, pAKT) are consistent with ablation of SHP2 mediated inhibitory signals and restoration of the key signalling events downstream of TCR/SLAM receptors that are required for adequate T cell function.

Conclusions

Collectively, these results support the further evaluation of SHP2 inhibitors as a potential alternative therapy for XLP patients.

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