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

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 kina...

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Autores principales: Winter, Sarah, Martin, Emmanuel, Boutboul, David, Lenoir, Christelle, Boudjemaa, Sabah, Petit, Arnaud, Picard, Capucine, Fischer, Alain, Leverger, Guy, Latour, Sylvain
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801500/
https://www.ncbi.nlm.nih.gov/pubmed/29282224
http://dx.doi.org/10.15252/emmm.201708292
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author Winter, Sarah
Martin, Emmanuel
Boutboul, David
Lenoir, Christelle
Boudjemaa, Sabah
Petit, Arnaud
Picard, Capucine
Fischer, Alain
Leverger, Guy
Latour, Sylvain
author_facet Winter, Sarah
Martin, Emmanuel
Boutboul, David
Lenoir, Christelle
Boudjemaa, Sabah
Petit, Arnaud
Picard, Capucine
Fischer, Alain
Leverger, Guy
Latour, Sylvain
author_sort Winter, Sarah
collection PubMed
description 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.
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spelling pubmed-58015002018-02-15 Loss of RASGRP1 in humans impairs T‐cell expansion leading to Epstein‐Barr virus susceptibility Winter, Sarah Martin, Emmanuel Boutboul, David Lenoir, Christelle Boudjemaa, Sabah Petit, Arnaud Picard, Capucine Fischer, Alain Leverger, Guy Latour, Sylvain EMBO Mol Med Research Articles 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. John Wiley and Sons Inc. 2018-01-08 2018-02 /pmc/articles/PMC5801500/ /pubmed/29282224 http://dx.doi.org/10.15252/emmm.201708292 Text en © 2017 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the Creative Commons Attribution 4.0 (http://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Research Articles
Winter, Sarah
Martin, Emmanuel
Boutboul, David
Lenoir, Christelle
Boudjemaa, Sabah
Petit, Arnaud
Picard, Capucine
Fischer, Alain
Leverger, Guy
Latour, Sylvain
Loss of RASGRP1 in humans impairs T‐cell expansion leading to Epstein‐Barr virus susceptibility
title 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_short 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
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5801500/
https://www.ncbi.nlm.nih.gov/pubmed/29282224
http://dx.doi.org/10.15252/emmm.201708292
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