The p.Arg63Trp polymorphism controls Vav1 functions and Foxp3 regulatory T cell development

J Exp Med. 2011 Oct 24;208(11):2183-91. doi: 10.1084/jem.20102191. Epub 2011 Sep 26.


CD4(+) regulatory T cells (T(reg) cells) expressing the transcription factor Foxp3 play a pivotal role in maintaining peripheral tolerance by inhibiting the expansion and function of pathogenic conventional T cells (T(conv) cells). In this study, we show that a locus on rat chromosome 9 controls the size of the natural T(reg) cell compartment. Fine mapping of this locus with interval-specific congenic lines and association experiments using single nucleotide polymorphisms (SNPs) identified a nonsynonymous SNP in the Vav1 gene that leads to the substitution of an arginine by a tryptophan (p.Arg63Trp). This p.Arg63Trp polymorphism is associated with increased proportion and absolute numbers of T(reg) cells in the thymus and peripheral lymphoid organs, without impacting the size of the T(conv) cell compartment. This polymorphism is also responsible for Vav1 constitutive activation, revealed by its tyrosine 174 hyperphosphorylation and increased guanine nucleotide exchange factor activity. Moreover, it induces a marked reduction in Vav1 cellular contents and a reduction of Ca(2+) flux after TCR engagement. Together, our data reveal a key role for Vav1-dependent T cell antigen receptor signaling in natural T(reg) cell development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Congenic
  • Arginine / genetics
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / physiology
  • Cells, Cultured
  • Chromosomes, Mammalian / genetics
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism*
  • HEK293 Cells
  • Humans
  • Polymorphism, Genetic*
  • Proto-Oncogene Proteins c-vav / genetics*
  • Proto-Oncogene Proteins c-vav / metabolism*
  • Rats
  • Rats, Inbred Lew
  • T-Lymphocytes, Regulatory / cytology
  • T-Lymphocytes, Regulatory / physiology*
  • Transplantation Chimera
  • Tryptophan / genetics


  • Forkhead Transcription Factors
  • Foxp3 protein, rat
  • Proto-Oncogene Proteins c-vav
  • VAV1 protein, human
  • Tryptophan
  • Arginine