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Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis.

ABSTRACT: In patients with rheumatoid arthritis (RA), CD4(+)T cells hyperproliferate during clonal expansion, differentiating into cytokine-producing effector cells that contribute to disease pathology. However, the metabolic underpinnings of this hyperproliferation remain unclear. In contrast to healthy T cells, naïve RA T cells had a defect in glycolytic flux due to the up-regulation of glucose-6-phosphate dehydrogenase (G6PD). Excess G6PD shunted glucose into the pentose phosphate pathway, resulting in NADPH (reduced form of nicotinamide adenine dinucleotide phosphate) accumulation and reactive oxygen species (ROS) consumption. With surplus reductive equivalents, RA T cells insufficiently activated the redox-sensitive kinase ataxia telangiectasia mutated (ATM), bypassed the G2/M cell cycle checkpoint, and hyperproliferated. Moreover, insufficient ATM activation biased T cell differentiation toward the T helper 1 (TH1) and TH17 lineages, imposing a hyperinflammatory phenotype. We have identified several interventions that replenish intracellular ROS, which corrected the abnormal proliferative behavior of RA T cells and successfully suppressed synovial inflammation. Thus, rebalancing glucose utilization and restoring oxidant signaling may provide a therapeutic strategy to prevent autoimmunity in RA.

SUBMITTER: Yang Z

PROVIDER: S-EPMC5074090 | biostudies-other | 2016 Mar

REPOSITORIES: biostudies-other

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Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis.

Yang Zhen Z Shen Yi Y Oishi Hisashi H Matteson Eric L EL Tian Lu L Goronzy Jörg J JJ Weyand Cornelia M CM

Science translational medicine 20160301 331

In patients with rheumatoid arthritis (RA), CD4(+)T cells hyperproliferate during clonal expansion, differentiating into cytokine-producing effector cells that contribute to disease pathology. However, the metabolic underpinnings of this hyperproliferation remain unclear. In contrast to healthy T cells, naïve RA T cells had a defect in glycolytic flux due to the up-regulation of glucose-6-phosphate dehydrogenase (G6PD). Excess G6PD shunted glucose into the pentose phosphate pathway, resulting in ...[more]

PMID: 27009267

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Project description:BackgroundRheumatoid arthritis is a chronic inflammatory disease with a strong MHC class II component and where many patients develop characteristic autoantibodies towards the noncoding amino acid citrulline. Such anti-citrullinated protein antibodies (ACPA) have recently been put forward as an independent predictive factor for treatment response by co-stimulation blockade by CTLA4-Ig (abatacept). We have performed a mechanism of action study to dissect T cell functionality in RA patients with long-standing disease undergoing abatacept treatment and the influence of ACPA status.ResultsPeripheral blood samples were collected from RA patients as they started CTLA4-Ig treatment and 3 and 6 months later. A general decrease of regulatory T cell subsets was observed in the cohort. Additionally within the ACPA-positive group significant down-regulation of all key T cell effector subsets including Th1, Th2, and Th17 was observed by analyzing cytokines by intracellular flow cytometry and in cell culture supernatants.RA synovial fluid samples were cultured in vitro in the presence or absence of CTLA4-Ig (abatacept). T cell cytokine production was diminished, but without increasing the functional capacity of CD4+CD25hi regulatory T cells as previously demonstrated in the context of TNF-blockade and anti-IL6R therapy.ConclusionsOur immunological study of T cell functionality in RA patients, both ACPA-positive and ACPA-negative starting biological therapy with the co-stimulation blockade abatacept (CTLA4-Ig) supports the recently published registry study implicating ACPA seropositivity as an independent predictive factor to treatment response as we observed the most striking effect on T cell subset modulation in ACPA-positive patients. These data further support the notion of RA as a disease with several sub-entities, where the ACPA-positive fraction represents a classical HLA-associated autoimmune disorder while ACPA-negative patients may have other driving forces apart from classical adaptive immune responses.

Project description:Infiltration of memory CD4+ T cells in synovial joints of Rheumatoid Arthritis (RA) patients has been reported since decades. Moreover, several genome wide association studies (GWAS) pinpointing a key genetic association between the HLA-DR locus and RA have led to the generally agreed hypothesis that CD4+ T cells are directly implicated in the disease. Still, RA is a heterogeneous disease and much effort has been made to understand its different facets. T cell differentiation is driven by mechanisms including antigen stimulation, co-stimulatory signals and cytokine milieu, all of which are abundant in the rheumatic joint, implying that any T cells migrating into the joint may be further affected locally. In parallel to the characterization and classification of T-cell subsets, the contribution of different effector T cells to RA has been investigated in numerous studies though sometimes with contradictory results. In particular, the frequency of Th1 and Th17 cells has been assessed in the synovial joints with various results that could, at least partly, be explained by the stage of the disease. For regulatory T cells, it is largely accepted that they accumulate in RA synovial fluid and that the equilibrium between regulatory T cells and effector cells is a key factor in controlling inflammation processes involved in RA. Recent phenotypic studies describe the possible implication of a novel subset of peripheral T helper cells (Tph) important for T-B cell cross talk and plasma cell differentiation in the RA joint of ACPA+ (autoantibodies against citrullinated proteins) RA patients. Finally, cytotoxic CD4+ T cells, historically described as increased in the peripheral blood of RA patients have attracted new attention in the last years. In view of the recently identified peripheral T-cell subsets, we will integrate immunological data as well as information on genetic variants and therapeutic strategy outcomes into our current understanding of the width of effector T cells. We will also integrate tissue-resident memory T cell aspects, and discuss similarities and differences with inflammatory conditions in skin (psoriasis) and mucosal organs (Crohn's disease).

Dataset Information

Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis.

Publications

Restoring oxidant signaling suppresses proarthritogenic T cell effector functions in rheumatoid arthritis.

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