Reduced TGF‑βR signaling results in increased T cell activation without autoinflammatory disease

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Abstract Transforming growth factor-β receptor (TGF-βR) signaling is important in regulating the proliferation and differentiation of CD4+ T cells, but how modulating the level of signaling can affect T cell fate remains unclear. We have created a mouse model of Loeys-Dietz syndrome (LDS), an autosomal dominant disease caused by mutations in genes encoding the TGF-βR, by targeting a missense mutation (M318R) to the endogenous murine Tgfbr1 locus. LDS patients exhibit an increased propensity for allergic disease, but no overt immunodeficiency or autoimmune disease. A higher percentage of CD4+ T cells in Tgfbr1M318R/+ mice exhibited a memory phenotype and produced enhanced levels of cytokines including IFN-γ, IL-13, IL-17, and IL-10 upon stimulation, but no autoimmunity was observed. In contrast, mice lacking TGF-βR2 specifically in T cells demonstrate exaggerated IFN-γ production and widespread autoinflammatory disease. While naïve CD4+ T cells from Tgfbr1M318R/+ mice were less likely to upregulate Foxp3 during in vitro culture with recombinant TGF-β, paradoxically, increased percentages and numbers of suppressive Foxp3+ regulatory T cells (Tregs) were observed in vivo, which may indicate a role for increased proliferation or survival of thymically-derived Tregs. The effects of the Tgfbr1M318R/+on T cells appear to be cell intrinsic. We observed no differences in T cells derived from WT bone marrow used to reconstitute irradiated Tgfbr1M318R/+ or WT hosts, while Tgfbr1M318R/+ bone marrow co-transferred with WT bone marrow into WT hosts gave rise to more activated CD4+ T cells and a higher frequency of Foxp3+ cells. These data suggest that partially abrogated TGF-β signaling leads to unexpected effects on T cell development and function.