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.;Roose, Jeroen P.

Matt Field

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.

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eLife

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2050-084X

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eLife Sciences

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DOI

10.7554/eLife.01020