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

Abstract

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 (T_H1)/T_H17/T follicular helper cell response with expression of <i>CCR6</i>, <i>IL21</i>, <i>TBX21</i>, <i>TNF</i>, <i>RORC</i>, <i>EGR2</i>, <i>TGFB1</i>, and <i>ICOS</i>, in the absence of <i>FOXP3</i>, <i>IL17</i>, and other cytokines. The cells transitioned to an <i>IFNG</i>-T_H1 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.