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...
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doaj-fc38f13a3f3f4e269eec41362be81d022021-08-02T10:05:35ZengWileyEMBO Molecular Medicine1757-46761757-46842018-02-0110218819910.15252/emmm.201708292Loss of RASGRP1 in humans impairs T‐cell expansion leading to Epstein‐Barr virus susceptibilitySarah Winter0Emmanuel Martin1David Boutboul2Christelle Lenoir3Sabah Boudjemaa4Arnaud Petit5Capucine Picard6Alain Fischer7Guy Leverger8Sylvain Latour9Laboratory of Lymphocyte Activation and Susceptibility to EBV infection Inserm UMR 1163 Paris FranceLaboratory of Lymphocyte Activation and Susceptibility to EBV infection Inserm UMR 1163 Paris FranceLaboratory of Lymphocyte Activation and Susceptibility to EBV infection Inserm UMR 1163 Paris FranceLaboratory of Lymphocyte Activation and Susceptibility to EBV infection Inserm UMR 1163 Paris FranceDepartment of Pathology Armand Trousseau Hospital Paris FranceDepartment of Hematology and Pediatric Oncology Armand Trousseau Hospital Paris FranceLaboratory of Lymphocyte Activation and Susceptibility to EBV infection Inserm UMR 1163 Paris FranceImagine Institut University Paris Descartes Sorbonne Paris Cité Paris FranceDepartment of Hematology and Pediatric Oncology Armand Trousseau Hospital Paris FranceLaboratory of Lymphocyte Activation and Susceptibility to EBV infection Inserm UMR 1163 Paris FranceAbstract 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.https://doi.org/10.15252/emmm.201708292Hodgkin lymphomaimmunodeficiencylymphocytesusceptibility to Epstein–Barr virusT‐cell proliferation |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Sarah Winter Emmanuel Martin David Boutboul Christelle Lenoir Sabah Boudjemaa Arnaud Petit Capucine Picard Alain Fischer Guy Leverger Sylvain Latour |
spellingShingle |
Sarah Winter Emmanuel Martin David Boutboul Christelle Lenoir Sabah Boudjemaa Arnaud Petit Capucine Picard Alain Fischer Guy Leverger Sylvain Latour Loss of RASGRP1 in humans impairs T‐cell expansion leading to Epstein‐Barr virus susceptibility EMBO Molecular Medicine Hodgkin lymphoma immunodeficiency lymphocyte susceptibility to Epstein–Barr virus T‐cell proliferation |
author_facet |
Sarah Winter Emmanuel Martin David Boutboul Christelle Lenoir Sabah Boudjemaa Arnaud Petit Capucine Picard Alain Fischer Guy Leverger Sylvain Latour |
author_sort |
Sarah Winter |
title |
Loss of RASGRP1 in humans impairs T‐cell expansion leading to Epstein‐Barr virus susceptibility |
title_short |
Loss of RASGRP1 in humans impairs T‐cell expansion leading to Epstein‐Barr virus susceptibility |
title_full |
Loss of RASGRP1 in humans impairs T‐cell expansion leading to Epstein‐Barr virus susceptibility |
title_fullStr |
Loss of RASGRP1 in humans impairs T‐cell expansion leading to Epstein‐Barr virus susceptibility |
title_full_unstemmed |
Loss of RASGRP1 in humans impairs T‐cell expansion leading to Epstein‐Barr virus susceptibility |
title_sort |
loss of rasgrp1 in humans impairs t‐cell expansion leading to epstein‐barr virus susceptibility |
publisher |
Wiley |
series |
EMBO Molecular Medicine |
issn |
1757-4676 1757-4684 |
publishDate |
2018-02-01 |
description |
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. |
topic |
Hodgkin lymphoma immunodeficiency lymphocyte susceptibility to Epstein–Barr virus T‐cell proliferation |
url |
https://doi.org/10.15252/emmm.201708292 |
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