title: The p.Arg63Trp polymorphism controls Vav1 functions and Foxp3 regulatory T cell development.
abstract: 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.
authors.affiliation: INSERM Unité 1043, Centre National de la Recherche Scientifique Unité 5282, Toulouse, France.
authors.forename: Céline
authors.initials: C
authors.lastname: Colacios
authors.forename: Audrey
authors.initials: A
authors.lastname: Casemayou
authors.forename: Anne S
authors.initials: AS
authors.lastname: Dejean
authors.forename: Frédérique
authors.initials: F
authors.lastname: Gaits-Iacovoni
authors.forename: Christophe
authors.initials: C
authors.lastname: Pedros
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bernard
authors.forename: Dominique
authors.initials: D
authors.lastname: Lagrange
authors.forename: Marcel
authors.initials: M
authors.lastname: Deckert
authors.forename: Lucille
authors.initials: L
authors.lastname: Lamouroux
authors.forename: Maja
authors.initials: M
authors.lastname: Jagodic
authors.forename: Tomas
authors.initials: T
authors.lastname: Olsson
authors.forename: Roland S
authors.initials: RS
authors.lastname: Liblau
authors.forename: Gilbert J
authors.initials: GJ
authors.lastname: Fournié
authors.forename: Abdelhadi
authors.initials: A
authors.lastname: Saoudi
mesh_terms: D000818:Animals; D020296:Animals, Congenic; D001120:Arginine / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000502:physiology; D002478:Cells, Cultured; D033481:Chromosomes, Mammalian / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D011110:Polymorphism, Genetic; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics* / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000502:physiology*; D018183:Transplantation Chimera; D014364:Tryptophan / Q000235:genetics
chemical_list: D051858:Forkhead Transcription Factors; C500522:Foxp3 protein, rat; D051567:Proto-Oncogene Proteins c-vav; C496618:VAV1 protein, human; D014364:Tryptophan; D001120:Arginine