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Loss of RASGRP1 in humans impairs T-cell expansion leading to Epstein-Barr virus susceptibility.

ABSTRACT: Inherited CTPS1, CD27, and CD70 deficiencies in humans have revealed key factors of T-lymphocyte expansion, a critical prerequisite for an efficient immunity to Epstein-Barr virus (EBV) infection. RASGRP1 is a T-lymphocyte-specific nucleotide exchange factor known to activate the pathway of MAP kinases (MAPK). A deleterious homozygous mutation in RASGRP1 leading to the loss RASGRP1 expression was identified in two siblings who both developed a persistent EBV infection leading to Hodgkin lymphoma. RASGRP1-deficient T cells exhibited defective MAPK activation and impaired proliferation that was restored by expression of wild-type RASGRP1. Similar defects were observed in T cells from healthy individuals when RASGRP1 was downregulated. RASGRP1-deficient T cells also exhibited decreased CD27-dependent proliferation toward CD70-expressing EBV-transformed B cells, a crucial pathway required for expansion of antigen-specific T cells during anti-EBV immunity. Furthermore, RASGRP1-deficient T cells failed to upregulate CTPS1, an important enzyme involved in DNA synthesis. These results show that RASGRP1 deficiency leads to susceptibility to EBV infection and demonstrate the key role of RASGRP1 at the crossroad of pathways required for the expansion of activated T lymphocytes.

SUBMITTER: Winter S

PROVIDER: S-EPMC5801500 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Loss of RASGRP1 in humans impairs T-cell expansion leading to Epstein-Barr virus susceptibility.

Winter Sarah S Martin Emmanuel E Boutboul David D Lenoir Christelle C Boudjemaa Sabah S Petit Arnaud A Picard Capucine C Fischer Alain A Leverger Guy G Latour Sylvain S

EMBO molecular medicine 20180201 2

Inherited CTPS1, CD27, and CD70 deficiencies in humans have revealed key factors of T-lymphocyte expansion, a critical prerequisite for an efficient immunity to Epstein-Barr virus (EBV) infection. RASGRP1 is a T-lymphocyte-specific nucleotide exchange factor known to activate the pathway of MAP kinases (MAPK). A deleterious homozygous mutation in <i>RASGRP1</i> leading to the loss RASGRP1 expression was identified in two siblings who both developed a persistent EBV infection leading to Hodgkin l ...[more]

PMID: 29282224

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Project description:The main target cells for Epstein-Barr virus (EBV) infection and persistence are B lymphocytes, although T and NK cells can also become infected. In this paper, we characterize the EBV present in 21 pediatric and adult patients who were treated in France for a range of diseases that involve infection of T or NK cells. Of these 21 cases, 5 pediatric patients (21%) and 11 adult patients (52%) were of Caucasian origin. In about 30% of the cases, some of the EBV genomes contain a large deletion. The deletions are different in every patient but tend to cluster near the BART region of the viral genome. Detailed investigation of a family in which several members have persistent T or NK cell infection by EBV indicates that the virus genome deletions arise or are selected independently in each individual patient. Genome sequence polymorphisms in the EBV in these T or NK cell diseases reflect the geographic origin of the patient and not a distinct type of EBV (the 21 cases studied included examples of both type 1 and type 2 EBV infection). Using virus produced from type 1 or type 2 EBV genomes cloned in bacterial artificial chromosome (BAC) vectors, we demonstrate infection of T cells in cord blood from healthy donors. Our results are consistent with transient infection of some T cells being part of normal asymptomatic infection by EBV in young children. IMPORTANCE EBV contributes to several types of human cancer. Some cancers and nonmalignant lymphoproliferative diseases involving T or NK cells contain EBV. These diseases are relatively frequent in Japan and China and have been shown sometimes to have deletions in the EBV genome in the disease cells. We identify further examples of deletions within the EBV genome associated with T or NK cell diseases, and we provide evidence that the virus genomes with these deletions are most likely selected in the individual cases, rather than being transmitted between people during infection. We demonstrate EBV infection of cord blood T cells by highly characterized, cloned EBV genomes and suggest that transient infection of T cells may be part of normal asymptomatic infection by EBV in young children.

Dataset Information

Loss of RASGRP1 in humans impairs T-cell expansion leading to Epstein-Barr virus susceptibility.

Publications

Loss of RASGRP1 in humans impairs T-cell expansion leading to Epstein-Barr virus susceptibility.

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