We found that intrathymic enrichment with IL-4 fine tunes signaling through the IL-4/IL-13 heteroreceptor (HR) in early thymic progenitors (ETPs), augments negative selection of self-reactive T cells, sustains a diverse T cell repertoire devoid of clones expressing disease-associated T cell receptor (TCR) genes, and protects the nonobese diabetic (NOD) mouse from T1D. Here, IL4 is linked to type 1 diabetes mellitus.