Loss of RASGRP 1 in humans impairs T‐cell expansion leading to Epstein‐Barr virus susceptibility

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.