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

Autoimmune diabetes is marked by sensitization to beta cell self-antigens in childhood. We longitudinally followed at-risk children from infancy and performed single-cell gene expression in b cell antigen-responsive CD4(+) T cells through pre-and established autoimmune phases. A striking divergence in the gene signature of beta cell antigenresponsive naive CD4(+) T cells from children who developed beta cell autoimmunity was found in infancy, well before the appearance of b cell antigen-specific memory T cells or autoantibodies. The signature resembled a pre-T helper 1 (T(H)1)/T(H)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-T(H)1 memory phenotype with the emergence of autoantibodies. We suggest that the divergent naive 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 beta cell autoimmunity.