title: Rasgrp1 mutation increases naive T-cell CD44 expression and drives mTOR-dependent accumulation of Helios⁺ T cells and autoantibodies.
abstract: Missense variants are a major source of human genetic variation. Here we analyze a new mouse missense variant, Rasgrp1(Anaef), with an ENU-mutated EF hand in the Rasgrp1 Ras guanine nucleotide exchange factor. Rasgrp1(Anaef) mice exhibit anti-nuclear autoantibodies and gradually accumulate a CD44(hi) Helios(+) PD-1(+) CD4(+) T cell population that is dependent on B cells. Despite reduced Rasgrp1-Ras-ERK activation in vitro, thymocyte selection in Rasgrp1(Anaef) is mostly normal in vivo, although CD44 is overexpressed on naïve thymocytes and T cells in a T-cell-autonomous manner. We identify CD44 expression as a sensitive reporter of tonic mTOR-S6 kinase signaling through a novel mouse strain, chino, with a reduction-of-function mutation in Mtor. Elevated tonic mTOR-S6 signaling occurs in Rasgrp1(Anaef) naïve CD4(+) T cells. CD44 expression, CD4(+) T cell subset ratios and serum autoantibodies all returned to normal in Rasgrp1(Anaef)Mtor(chino) double-mutant mice, demonstrating that increased mTOR activity is essential for the Rasgrp1(Anaef) T cell dysregulation. DOI: http://dx.doi.org/10.7554/eLife.01020.001.
authors: Department of Immunology, John Curtin School of Medical Research, The Australian National University, Canberra, Australia.
authors: Stephen R
authors: SR
authors: Daley
authors: Kristen M
authors: KM
authors: Coakley
authors: Daniel Y
authors: DY
authors: Hu
authors: Katrina L
authors: KL
authors: Randall
authors: Craig N
authors: CN
authors: Jenne
authors: Andre
authors: A
authors: Limnander
authors: Darienne R
authors: DR
authors: Myers
authors: Noelle K
authors: NK
authors: Polakos
authors: Anselm
authors: A
authors: Enders
authors: Carla
authors: C
authors: Roots
authors: Bhavani
authors: B
authors: Balakishnan
authors: Lisa A
authors: LA
authors: Miosge
authors: Geoff
authors: G
authors: Sjollema
authors: Edward M
authors: EM
authors: Bertram
authors: Matthew A
authors: MA
authors: Field
authors: Yunli
authors: Y
authors: Shao
authors: T Daniel
authors: TD
authors: Andrews
authors: Belinda
authors: B
authors: Whittle
authors: S Whitney
authors: SW
authors: Barnes
authors: John R
authors: JR
authors: Walker
authors: Jason G
authors: JG
authors: Cyster
authors: Christopher C
authors: CC
authors: Goodnow
authors: Jeroen P
authors: JP
authors: Roose
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D020832:EF Hand Motifs; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000502:physiology*; D018960:Hyaluronan Receptors / Q000276:immunology*; D051379:Mice; D009154:Mutation; D013601:T-Lymphocytes / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000502:physiology*
chemical_list: D001323:Autoantibodies; C476399:Cd44 protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D018960:Hyaluronan Receptors; C112278:Rasgrp1 protein, mouse; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases
keywords: ENU mutant; RasGRP1; T lymphoctes; autoimmunity; mTOR; signaling