The T cell receptor associated transmembrane adaptor 1 regulates the threshold for activation of naïve human CD4⁺ T...

T cell fate is partly determined by T cell receptor (TCR) affinity for its cognate peptide ligand. During thymic selection, CD4⁺ T cells with higher affinity for self-antigens are more likely to be deleted or become FOXP3⁺ natural T regulatory (nTreg) cells. However, downstream transmembrane adaptor proteins such as the T cell receptor associated transmembrane adaptor 1 (TRAT1) also modulate T cell activation. Here we show that TRAT1 decreases the activation threshold of human naïve CD4⁺ T cells and mediates TCR activation leading to transient FOXP3 expression via FOXO3A. Individuals at high risk for autoimmune type 1 diabetes (T1D) had increased proportions of CD4⁺ T cells with elevated TRAT1 expression in their naïve CD4⁺ T cell compartment. Naïve CD4⁺ T cells transduced with an insulin-specific TCR-TRAT1 construct exhibited enhanced proliferation, even in the absence of exogenously added insulin peptide, and showed heightened sensitivity to low doses of insulin peptide. These findings reveal an additional layer of T cell reactivity regulation independent of TCR affinity, which may underlie homeostatic and pathogenic functions of human T cells.