Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Functional Plasticity of Regulatory T Cell Function

ABSTRACT: Regulatory T cells (Tregs) can suppress a wide variety of cell types, in diverse organ sites and inflammatory conditions. While Tregs possess multiple suppressive mechanisms, the number required for maximal function is unclear. Furthermore, whether any inter-relationship orcross-regulatory mechanisms exist that areused to orchestrate and control their utilization is unknown. Here we assessed the functional capacity of Tregs lacking the ability to secrete both interleukin-10 (IL-10) and IL-35, which individually are required for maximal Treg activity. Surprisingly, IL-10/IL-35-double deficient Tregswere fully functionalin vitro and in vivo. Loss of IL-10 and IL-35 was compensated for by a concurrent increase in cathepsin E (CTSE) expression, enhanced TRAIL (Tnfsf10)expression and soluble TRAIL release, rendering IL-10/IL-35-double deficient Tregsfunctionally dependent on TRAIL in vitro and in vivo. Lastly, while C57BL/6 Tregs are IL-10/IL-35-dependent, Balb/c Tregs, which express high levels of CTSE and enhanced TRAIL expression, are TRAIL-dependent.These data reveal that cross-regulatory pathways exist, which control the utilization of suppressive mechanisms,thereby providing Tregfunctional plasticity. Isolate natural Tregs from the different knockout mouse

ORGANISM(S): Mus musculus

SUBMITTER: David Finkelstein

PROVIDER: E-GEOD-29262 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

The plasticity of regulatory T cell function.

Pillai Meenu R MR Collison Lauren W LW Wang Xiaohua X Finkelstein David D Rehg Jerold E JE Boyd Kelli K Szymczak-Workman Andrea L AL Doggett Teresa T Griffith Thomas S TS Ferguson Thomas A TA Vignali Dario A A DA

Journal of immunology (Baltimore, Md. : 1950) 20111017 10

Regulatory T cells (T(regs)) can suppress a wide variety of cell types, in diverse organ sites and inflammatory conditions. Whereas T(regs) possess multiple suppressive mechanisms, the number required for maximal function is unclear. Furthermore, whether any interrelationship or cross-regulatory mechanisms exist to orchestrate and control their utilization is unknown. In this study, we assessed the functional capacity of T(regs) lacking the ability to secrete both IL-10 and IL-35, which individu ...[more]

PMID: 22013112

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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

Dataset Information

Functional Plasticity of Regulatory T Cell Function

Publications

The plasticity of regulatory T cell function.

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