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

Abstract

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 Nur77high 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.

Interruption of thymic activity in adults improves responses to tumor immunotherapy

“…Our detailed cellular analysis confirms our prediction that adult thymectomy alters both Tconv and Treg composition, to somewhat similar extent, and imposes a similar bias for activated/effector/memory phenotype in the peripheral T cell pool. Our results also confirms that absence of tTreg output is not compensated by differentiation of pTreg in the periphery, as was predicted by the earlier finding that RTE are the precursors of bona fide Treg differentiated in the periphery (7,8). This finding is also consistent with the compromised return to homeostasis upon Treg perturbation, which we document in TxT animals.…”

“…We extended this finding by performing adoptive transfer into lymphoreplete animals. While donor cells and newly differentiated Treg are barely detectable in lymphoreplete recipients, these are readily measurable when using DEREG recipient animals partially deleted of endogenous Treg (8). In the latter assay, as in lympho-deficient mice, cells isolated from TxT mice performed poorly ( Fig 2B).…”

“…Most analyses on the impact on health of thymic surgical ablation, physiological atrophy or involution, focused on the ensuing restricted repertoire of effector T cells, which satisfyingly explains a reduced efficiency in targeting infectious agents. However, thymic output is also required to replenish the pool of peripheral Treg, through both the production of Treg already differentiated in the thymus (tTreg) (2) and the production of immature T cells that are the preferential precursors of bona fide Treg differentiated in the periphery (6)(7)(8).…”

Control of regulatory T‐cell differentiation and function by T‐cell receptor signalling and Foxp3 transcription factor complexes

“…ROR‐γt + Treg are considered to be pTreg, as they do not express Helios and are induced by gut microbiota, while Helios + Treg are regarded as tTreg. However, it is debated how specific these markers are, and a recent single cell study showed that conventional T‐cells can generate both Helios + and ROR‐γt + Treg in the colon …”

Tissue regulatory T cells

“…64 Furthermore, transferring LN Teffs to Treg-depleted mice, Teffs can acquire a RORct + Helios À and Helios + colonic Treg phenotype, depending on the level of nerve growth factor IB (otherwise known as Nur77). 65 Nur77 functions as an important regulator of cell survival, inflammation, but also as an early reporter for antigen-specific signalling. 66 Taken together, both tTregs and pTregs contribute to the establishment of colonic Tregs.…”