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

被引：14

作者：

Colacios, Celine ^{[1
,2
,3
]}

Casemayou, Audrey ^{[1
,2
,3
]}

Dejean, Anne S. ^{[1
,2
,3
]}

Gaits-Iacovoni, Frederique ^{[4
]}

Pedros, Christophe ^{[1
,2
,3
]}

Bernard, Isabelle ^{[1
,2
,3
]}

Lagrange, Dominique ^{[1
,2
,3
]}

Deckert, Marcel ^{[5
]}

Lamouroux, Lucille ^{[1
,2
,3
]}

Jagodic, Maja ^{[6
]}

Olsson, Tomas ^{[6
]}

Liblau, Roland S. ^{[1
,2
,3
]}

Fournie, Gilbert J. ^{[1
,2
,3
]}

Saoudi, Abdelhadi ^{[1
,2
,3
]}

机构：

[1] Inst Natl Sante & Rech Med, U1043, F-31300 Toulouse, France

[2] Ctr Natl Rech Sci, Unite 5282, F-31300 Toulouse, France

[3] Univ Toulouse 3, Univ Toulouse, Ctr Physiopathol Toulouse Purpan, F-31300 Toulouse, France

[4] Inst Natl Sante & Rech Med, Unite Mixte Rech 1048, Inst Malad Metabol & Cardiovasc Toulouse, F-31300 Toulouse, France

[5] Univ Nice Sophia Antipolis, Inst Natl Sante & Rech Med, U1038, F-06202 Nice, France

[6] Karolinska Inst, Dept Clin Neurosci, Neuroimmunol Unit, S-17176 Stockholm, Sweden

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2011年 / 208卷 / 11期

基金：

瑞典研究理事会;

关键词：

DIFFERENTIAL REQUIREMENT; TYROSINE PHOSPHORYLATION; BROWN-NORWAY; ACTIVATION; PROTEINS; LINEAGE; ANTIGEN; RATS; SELF; AUTOINHIBITION;

D O I：

10.1084/jem.20102191

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

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.

引用

页码：2183 / 2191

页数：9

共 31 条

[1]

Structural basis for relief of autoinhibition of the Dbl homology domain of proto-oncogene Vav by tyrosine phosphorylation [J].