Developmental and cellular age direct conversion of CD4(+) T cells into RORγ(+) or Helios(+) colon Treg cells

RORγ(+) and Helios(+) Treg cells in the colon are phenotypically and functionally distinct, but their origins and relationships are poorly understood. In monocolonized and normal mice, single-cell RNA-seq revealed sharing of TCR clonotypes between these Treg cell populations, potentially denoting a common progenitor. In a polyclonal Treg cell replacement system, naive conventional CD4(+) (Tconv) cells, but not pre-existing tTregs, could differentiate into RORγ(+) pTregs upon interaction with gut microbiota. A smaller proportion of Tconv cells converted into Helios(+) pTreg cells, but these dominated when the Tconv cells originated from preweaning mice. T cells from infant mice were predominantly immature, insensitive to RORγ-inducing bacterial cues and to IL6, and showed evidence of higher TCR-transmitted signals, which are also characteristics of recent thymic emigrants (RTEs). Correspondingly, transfer of adult RTEs or Nur77(high) Tconv cells mainly yielded Helios(+) pTreg cells, recapitulating the infant/adult difference. Thus, CD4(+) Tconv cells can differentiate into both RORγ(+) and Helios(+) pTreg cells, providing a physiological adaptation of colonic Treg cells as a function of the age of the cell or of the individual.