| Autor: |
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 |
| Jazyk: |
angličtina |
| Rok vydání: |
2013 |
| Předmět: |
|
| Zdroj: |
eLife, Vol 2 (2013) |
| Druh dokumentu: |
article |
| ISSN: |
2050-084X |
| DOI: |
10.7554/eLife.01020 |
| Popis: |
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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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