eLife (Dec 2013)
Rasgrp1 mutation increases naïve 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 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 Walker,
- Jason G Cyster,
- Christopher C Goodnow,
- Jeroen P Roose
Affiliations
- Stephen R Daley
- Department of Immunology, John Curtin School of Medical Research, The Australian National University, Canberra, Australia
- Kristen M Coakley
- Department of Anatomy, University of California, San Francisco, San Francisco, United States
- Daniel Y Hu
- Department of Immunology, John Curtin School of Medical Research, The Australian National University, Canberra, Australia
- Katrina L Randall
- Department of Immunology, John Curtin School of Medical Research, The Australian National University, Canberra, Australia; Department of Immunology, Canberra Hospital and ANU Medical School, The Australian National University, Canberra, Australia
- Craig N Jenne
- Institute of Infection, Immunity and Inflammation, University of Calgary, Calgary, Canada
- Andre Limnander
- Department of Anatomy, University of California, San Francisco, San Francisco, United States
- Darienne R Myers
- Department of Anatomy, University of California, San Francisco, San Francisco, United States
- Noelle K Polakos
- Department of Anatomy, University of California, San Francisco, San Francisco, United States
- Anselm Enders
- Department of Immunology, John Curtin School of Medical Research, The Australian National University, Canberra, Australia
- Carla Roots
- Department of Immunology, John Curtin School of Medical Research, The Australian National University, Canberra, Australia
- Bhavani Balakishnan
- Australian Phenomics Facility, John Curtin School of Medical Research, The Australian National University, Canberra, Australia
- Lisa A Miosge
- Department of Immunology, John Curtin School of Medical Research, The Australian National University, Canberra, Australia
- Geoff Sjollema
- Australian Phenomics Facility, John Curtin School of Medical Research, The Australian National University, Canberra, Australia
- Edward M Bertram
- Department of Immunology, John Curtin School of Medical Research, The Australian National University, Canberra, Australia; Australian Phenomics Facility, John Curtin School of Medical Research, The Australian National University, Canberra, Australia
- Matthew A Field
- Department of Immunology, John Curtin School of Medical Research, The Australian National University, Canberra, Australia
- Yunli Shao
- Department of Immunology, John Curtin School of Medical Research, The Australian National University, Canberra, Australia
- T Daniel Andrews
- Department of Immunology, John Curtin School of Medical Research, The Australian National University, Canberra, Australia
- Belinda Whittle
- Australian Phenomics Facility, John Curtin School of Medical Research, The Australian National University, Canberra, Australia
- S Whitney Barnes
- Department of Genetics, Genomics Institute, Novartis Research Foundation, San Diego, United States
- John R Walker
- Department of Genetics, Genomics Institute, Novartis Research Foundation, San Diego, United States
- Jason G Cyster
- Department of Microbiology and Immunology, Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, United States
- Christopher C Goodnow
- Department of Immunology, John Curtin School of Medical Research, The Australian National University, Canberra, Australia; Australian Phenomics Facility, John Curtin School of Medical Research, The Australian National University, Canberra, Australia
- Jeroen P Roose
- Department of Anatomy, University of California, San Francisco, San Francisco, United States
- DOI
- https://doi.org/10.7554/eLife.01020
- Journal volume & issue
-
Vol. 2
Abstract
Missense variants are a major source of human genetic variation. Here we analyze a new mouse missense variant, Rasgrp1Anaef, with an ENU-mutated EF hand in the Rasgrp1 Ras guanine nucleotide exchange factor. Rasgrp1Anaef mice exhibit anti-nuclear autoantibodies and gradually accumulate a CD44hi Helios+ PD-1+ CD4+ T cell population that is dependent on B cells. Despite reduced Rasgrp1-Ras-ERK activation in vitro, thymocyte selection in Rasgrp1Anaef 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 Rasgrp1Anaef naïve CD4+ T cells. CD44 expression, CD4+ T cell subset ratios and serum autoantibodies all returned to normal in Rasgrp1AnaefMtorchino double-mutant mice, demonstrating that increased mTOR activity is essential for the Rasgrp1Anaef T cell dysregulation.
Keywords
