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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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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