Open AccessLoss of RASGRP 1 in humans impairs T‐cell expansion leading to Epstein‐Barr virus susceptibility
Author(s) -
Winter Sarah,
Martin Emmanuel,
Boutboul David,
Lenoir Christelle,
Boudjemaa Sabah,
Petit Arnaud,
Picard Capucine,
Fischer Alain,
Leverger Guy,
Latour Sylvain
Publication year - 2018
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201708292
Subject(s) - lymphocyte , medicine , immunology
Inherited CTPS 1, CD 27, and CD 70 deficiencies in humans have revealed key factors of T‐lymphocyte expansion, a critical prerequisite for an efficient immunity to Epstein–Barr virus ( EBV ) infection. RASGRP 1 is a T‐lymphocyte‐specific nucleotide exchange factor known to activate the pathway of MAP kinases (MAPK). A deleterious homozygous mutation in RASGRP 1 leading to the loss RASGRP 1 expression was identified in two siblings who both developed a persistent EBV infection leading to Hodgkin lymphoma. RASGRP 1‐deficient T cells exhibited defective MAPK activation and impaired proliferation that was restored by expression of wild‐type RASGRP 1. Similar defects were observed in T cells from healthy individuals when RASGRP 1 was downregulated. RASGRP 1‐deficient T cells also exhibited decreased CD 27‐dependent proliferation toward CD 70‐expressing EBV ‐transformed B cells, a crucial pathway required for expansion of antigen‐specific T cells during anti‐ EBV immunity. Furthermore, RASGRP 1‐deficient T cells failed to upregulate CTPS 1, an important enzyme involved in DNA synthesis. These results show that RASGRP 1 deficiency leads to susceptibility to EBV infection and demonstrate the key role of RASGRP 1 at the crossroad of pathways required for the expansion of activated T lymphocytes.