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Expression profile of cultured CD4 T cells

ABSTRACT: After activation via TCR, naïve CD4 T cells differentiate into several subsets including effector helper T cells and TGF-b-dependent inducible regulatory T (Treg) cells. These differentiated CD4 T cell subsets are more plastic than have previously been assumed to be, and some transdifferentiations among subsets have been reported. However, Th1 cells are one of the most stable subsets, and reprogramming of Th1 to Treg cells, especially underlining mechanism(s) of such conversion, has not been investigated in depth. Here we established a culture method of inducing Foxp3 expression from differentiated Th1 cells. This is achieved simply by resting Th1 cells in the absence of TCR ligation before stimulation in the presence of TGF-b. We named these Th1-derived Foxp3+ cells Th1reg cells. Th1reg cells showed an iTreg-like phenotype and suppressive ability. Th1reg cells induced with vitamin C showed high stability of Foxp3 expression in vitro and in vivo. Th1reg cells could also be induced from in vivo-developed Th1 cells prepared from mice with graft versus host disease. Surprisingly, the resting process did not induce appreciable change in epigenetic modifications at the Foxp3 locus, but down-regulated the mTORC1 activity of Th1 cells. Shift from glycolysis, downstream of the mTORC1 pathway, to oxidative phosphorylation-dependent metabolism was important for the induction of Th1reg cells. Both expression and TGF-b-induced phosphorylation of Smad2/3 were impaired in Th1 cells, and inhibition of mTORC1 restored the phosphorylation. Our study would lead to the development of a novel therapy for Th1-type aberrant inflammation.

ORGANISM(S): Mus musculus

PROVIDER: GSE110124 | GEO | 2018/02/06

REPOSITORIES: GEO

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Project description:The mechanistic target of rapamycin (mTOR) pathway integrates diverse environmental inputs, including immune signals and metabolic cues, to direct T cell fate decisions1. Activation of mTOR, comprised of mTORC1 and mTORC2 complexes, delivers an obligatory signal for proper activation and differentiation of effector CD4+ T cells2,3, whereas in the regulatory T cell (Treg) compartment, the Akt-mTOR axis is widely acknowledged as a crucial negative regulator of Treg de novo differentiation4-8 and population expansion9. However, whether mTOR signaling affects the homeostasis and function of Tregs remains largely unexplored. Here we show that mTORC1 signaling is a pivotal positive determinant of Treg function. Tregs have elevated steady-state mTORC1 activity compared to naïve T cells. Signals via T cell receptor (TCR) and IL-2 provide major inputs for mTORC1 activation, which in turn programs suppressive function of Tregs. Disruption of mTORC1 through Treg-specific deletion of the essential component Raptor leads to a profound loss of Treg suppressive activity in vivo and development of a fatal early-onset inflammatory disorder. Mechanistically, Raptor/mTORC1 signaling in Tregs promotes cholesterol/lipid metabolism, with the mevalonate pathway particularly important for coordinating Treg proliferation and upregulation of suppressive molecules CTLA-4 and ICOS to establish Treg functional competency. In contrast, mTORC1 does not directly impact the expression of Foxp3 or anti- and pro-inflammatory cytokines in Tregs, suggesting a non-conventional mechanism for Treg functional regulation. Lastly, we provide evidence that mTORC1 maintains Treg function partly through inhibiting the mTORC2 pathway. Our results demonstrate that mTORC1 acts as a fundamental ‘rheostat’ in Tregs to link immunological signals from TCR and IL-2 to lipogenic pathways and functional fitness, and highlight a central role of metabolic programming of Treg suppressive activity in immune homeostasis and tolerance. We used microarrays to explore the gene expression profiles differentially expressed in regulatory T-cells from wild-type and CD4(cre) x Raptor(fl/fl) mice

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Expression profile of cultured CD4 T cells

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