A divergent population of autoantigen-responsive CD4 + T cells in infants prior to β cell autoimmunity.

Autoimmune diabetes is marked by sensitization to β cell self-antigens in childhood. We longitudinally followed at-risk children from infancy and performed single-cell gene expression in β cell antigen-responsive CD4+ T cells through pre- and established autoimmune phases. A striking divergence in the gene signature of β cell antigen-responsive naïve CD4+ T cells from children who developed β cell autoimmunity was found in infancy, well before the appearance of β cell antigen-specific memory T cells or autoantibodies. The signature resembled a pre-T helper 1 (TH 1)/TH 17/T follicular helper cell response with expression of CCR6 , IL21 , TBX21 , TNF , RORC , EGR2 , TGFB1 , and ICOS , in the absence of FOXP3 , IL17 , and other cytokines. The cells transitioned to an IFNG -TH 1 memory phenotype with the emergence of autoantibodies. We suggest that the divergent naïve T cell response is a consequence of genetic or environmental priming during unfavorable perinatal exposures and that the signature will guide future efforts to detect and prevent β cell autoimmunity.