Inhibition of Rag GTPase signaling in mice suppresses B cell responses and lymphomagenesis with minimal detrimental trade-offs

B lymphocytes are exquisitely sensitive to fluctuations in nutrient signaling by the Rag GTPases, and 15% of follicular lymphomas (FLs) harbor activating mutations in RRAGC. Hence, a potential therapeutic approach against malignant B cells is to inhibit Rag GTPase signaling, but because such inhibitors are still to be developed, efficacy and safety remain unknown. We generated knockin mice expressing a hypomorphic variant of RagC (Q119L); RagCQ119L/+ mice are viable and show attenuated nutrient signaling. B lymphocyte activation is cell-intrinsically impaired in RagCQ119L/+ mice, which also show significant suppression of genetically induced lymphomagenesis and autoimmunity. Surprisingly, no overt systemic trade-offs or phenotypic alterations caused by partial suppression of nutrient signaling are seen in other organs, and RagCQ119L/+ mice show normal longevity and normal age-dependent health decline. These results support the efficacy and safety of moderate inhibition of nutrient signaling against pathological B cells. [Display omitted] •Knockin mice expressing a hypomorphic form of the RagC GTPase (Q119L) are viable•RagCQ119L/+ mice show attenuated nutrient signaling-mTORC1 activity•Lymphomagenesis and self-reactivity are delayed when induced in RagCQ119L/+ mice•Aside from B cells, RagCQ119L/+ mice show minimal defects and a normal lifespan By generating knockin mice expressing a hypomorphic variant of the RagC GTPase, Ortega-Molina et al. show that partial inhibition of nutrient signaling may be a safe and efficacious approach against pathogenic B cells and B cell lymphomas.