Transcriptomic conservation defines autoimmune stem-like T cells and uncovers their dependence on Apex1

Stem-like T cells (T STEM ) critically govern autoimmune responses. Unlike individual transcriptional master regulators of specialized T cells, the primary molecular determinant of T STEM , Tcf1, is shared with naive and other T cells. To unequivocally identify autoimmune T STEM , we established transcriptomic characteristics conserved across multiple immunological settings. We leveraged such conserved features to faithfully distinguish T STEM arising de novo among other Tcf1 + T cells and confirmed their autoimmune functions in vivo in a model of multiple sclerosis. We further detected the transcriptomically identifiable T STEM in corresponding human diseases, and among such T cells we uncovered a specifically increased expression of apurinic/apyrimidinic endodeoxyribonuclease 1 ( APEX1 ). By rigorously investigating Apex1-deficient T STEM in a disease model, we confirmed indispensable roles of Apex1 in governing the disease-producing functions of autoimmune T STEM . Thus, we established conserved features of autoimmune T STEM across species barriers and uncovered APEX1/Apex1 as a functional determinant of T STEM .