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Missense variants are a major source of human genetic variation. Here we analyze a new mouse missense variant,  Rasgrp1   Anaef  , with an ENU-mutated EF hand in the Rasgrp1 Ras guanine nucleotide exchange factor.  Rasgrp1   Anaef   mice exhibit anti-nuclear autoantibodies and gradually accumulate a CD44 hi  Helios +  PD-1 +  CD4 +  T cell population that is dependent on B cells. Despite reduced Rasgrp1-Ras-ERK activation in vitro, thymocyte selection in  Rasgrp1   Anaef   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  Rasgrp1   Anaef   naïve CD4 +  T cells. CD44 expression, CD4 +  T cell subset ratios and serum autoantibodies all returned to normal in  Rasgrp1   Anaef   Mtor   chino   double-mutant mice, demonstrating that increased mTOR activity is essential for the  Rasgrp1   Anaef   T cell dysregulation.

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