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

Daley, Stephen R., Coakley, Kristen M., Hu, Daniel Y., Randall, Katrina L., Jenne, Craig N., Limnander, Andre, Myers, Darienne R., Polakos, Noelle K., Enders, Anselm, Roots, Carla, Balakishnan, Bhavani, Miosge, Lisa A., Sjollema, Geoff, Bertram, Edward M., Field, Matthew A., Shao, Yunli, Andrews, T. Daniel, Whittle, Belinda, Barnes, S. Whitney, Walker, John R., Cyster, Jason G., Goodnow, Christopher C., and Roose, Jeroen P. (2013) Rasgrp1 mutation increases naïve T-cell CD44 expression and drives mTOR-dependent accumulation of Helios⁺ T cells and autoantibodies. eLife, 2. e01020. pp. 1-26.

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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.

Item ID: 43581
Item Type: Article (Research - C1)
ISSN: 2050-084X
Keywords: ENU mutant; RasGRP1; T lymphoctes; autoimmunity; mTOR; signaling
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Copyright © Daley et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.


Funders: Sandler Program in Basic Science (SPBS), National Institutes of Health (NIH), Wellcome Trust (WT), Department of Innovation, Industry, Science and Research and Tertiary Education (DIISRTE), Ramasciotti Foundation (RF), National Health and Medical Research Council (NHMRC)
Projects and Grants: NIH K01CA113367, NIH ARRA supplement, R56-AI095292, WT 082030/B/07/Z, NHMRC GNT1035858, NIH 1R03AR062783-01A1, NIH R01-AI74847, NIH R01 AI52127, NIH U54 AI054523
Date Deposited: 07 Sep 2016 23:31
FoR Codes: 06 BIOLOGICAL SCIENCES > 0601 Biochemistry and Cell Biology > 060102 Bioinformatics @ 25%
06 BIOLOGICAL SCIENCES > 0604 Genetics > 060408 Genomics @ 25%
11 MEDICAL AND HEALTH SCIENCES > 1107 Immunology > 110706 Immunogenetics (incl Genetic Immunology) @ 50%
SEO Codes: 92 HEALTH > 9201 Clinical Health (Organs, Diseases and Abnormal Conditions) > 920108 Immune System and Allergy @ 100%
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