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Notch controls the magnitude of T helper cell responses by promoting cellular longevity.

ABSTRACT: Generation of effective immune responses requires expansion of rare antigen-specific CD4(+) T cells. The magnitude of the responding population is ultimately determined by proliferation and survival. Both processes are tightly controlled to limit responses to innocuous antigens. Sustained expansion occurs only when innate immune sensors are activated by microbial stimuli or by adjuvants, which has important implications for vaccination. The molecular identity of the signals controlling sustained T-cell responses is not fully clear. Here, we describe a prominent role for the Notch pathway in this process. Coactivation of Notch allows accumulation of far greater numbers of activated CD4(+) T cells than stimulation via T-cell receptor and classic costimulation alone. Notch does not overtly affect cell cycle entry or progression of CD4(+) T cells. Instead, Notch protects activated CD4(+) T cells against apoptosis after an initial phase of clonal expansion. Notch induces a broad antiapoptotic gene expression program that protects against intrinsic, as well as extrinsic, apoptosis pathways. Both Notch1 and Notch2 receptors and the canonical effector RBPJ (recombination signal binding protein for immunoglobulin kappa J region) are involved in this process. Correspondingly, CD4(+) T-cell responses to immunization with protein antigen are strongly reduced in mice lacking these components of the Notch pathway. Our findings, therefore, show that Notch controls the magnitude of CD4(+) T-cell responses by promoting cellular longevity.

SUBMITTER: Helbig C

PROVIDER: S-EPMC3384214 | biostudies-literature | 2012 Jun

REPOSITORIES: biostudies-literature

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Notch controls the magnitude of T helper cell responses by promoting cellular longevity.

Helbig Christina C Gentek Rebecca R Backer Ronald A RA de Souza Yevan Y Derks Ingrid A M IA Eldering Eric E Wagner Koen K Jankovic Dragana D Gridley Thomas T Moerland Perry D PD Flavell Richard A RA Amsen Derk D

Proceedings of the National Academy of Sciences of the United States of America 20120521 23

Generation of effective immune responses requires expansion of rare antigen-specific CD4(+) T cells. The magnitude of the responding population is ultimately determined by proliferation and survival. Both processes are tightly controlled to limit responses to innocuous antigens. Sustained expansion occurs only when innate immune sensors are activated by microbial stimuli or by adjuvants, which has important implications for vaccination. The molecular identity of the signals controlling sustained ...[more]

PMID: 22615412

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Project description:BackgroundT helper cells in patients with autoimmune disease of idiopathic inflammatory myopathies (IIM) are characterized with the proinflammatory phenotypes. The underlying mechanisms remain unknown.MethodsRNA sequencing was performed for differential expression genes. Gene expression in CD4+ T-cells was confirmed by quantitative real-time PCR. CD4+ T-cells from IIM patients or healthy controls were evaluated for metabolic activities by Seahorse assay. Glucose uptake, T-cell proliferation and differentiation were evaluated and measured by flow cytometry. Human CD4+ T-cells treated with iron chelators or Pfkfb4 siRNA were measured for glucose metabolism, proliferation and differentiation. Signalling pathway activation was evaluated by western blot and flow cytometry. Mouse model of experimental autoimmune myositis (EAM) were induced and treated with iron chelator or rapamycin. CD4+ T-cell differentiation and muscle inflammation in the EAM mice were evaluated.ResultsRNA-sequencing analysis revealed that iron was involved with glucose metabolism and CD4+ T-cell differentiation. IIM patient-derived CD4+ T-cells showed enhanced glycolysis and mitochondrial respiration, which was inhibited by iron chelation. CD4+ T-cells from patients with IIM was proinflammatory and iron chelation suppressed the differentiation of interferon gamma (IFNγ)- and interleukin (IL)-17A-producing CD4+ T-cells, which resulted in an increased percentage of regulatory T (Treg) cells. Mechanistically, iron promoted glucose metabolism by an upregulation of PFKFB4 through AKT-mTOR signalling pathway. Notably, the knockdown of Pfkfb4 decreased glucose influx and thus suppressed the differentiation of IFNγ- and IL-17A-producing CD4+ T-cells. In vivo, iron chelation inhibited mTOR signalling pathway and reduced PFKFB4 expression in CD4+ T-cells, resulting in reduced proinflammatory IFNγ- and IL-17A-producing CD4+ T-cells and increased Foxp3+ Treg cells, leading to ameliorated muscle inflammation.ConclusionsIron directs CD4+ T-cells into a proinflammatory phenotype by enhancing glucose metabolism. Therapeutic targeting of iron metabolism should have the potential to normalize glucose metabolism in CD4+ T-cells and reverse their proinflammatory phenotype in IIM.

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Notch controls the magnitude of T helper cell responses by promoting cellular longevity.

Publications

Notch controls the magnitude of T helper cell responses by promoting cellular longevity.

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