Rasgrp1 mutation increases naive T-cell CD44 expression and drives mTOR-dependent accumulation of Helios(+) T cells and autoantibodies

Stephen R Daley, Kristen M Coakley, Daniel Y Hu, Katrina L Randall, Craig N Jenne, Andre Limnander, Darienne R Myers, Noelle K Polakos, Anselm Enders, Carla M Roots, Bhavani Balakishnan, Lisa A Miosge, Geoff Sjollema, Edward M Bertram, Matthew A Field, Yunli Shao, T Daniel Andrews, Belinda Whittle, S Whitney Barnes, John R WalkerJason G Cyster, Chris C Goodnow, Jeroen P Roose

Research output: Contribution to journalArticleResearchpeer-review

36 Citations (Scopus)

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 naive 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) naive 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.
Original languageEnglish
Pages (from-to)1 - 26
Number of pages26
JournaleLife
Volume2
DOIs
Publication statusPublished - 2013
Externally publishedYes

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