Regulation of T cell homeostasis by JAKs and STATs

Ross, Jeremy A.; Nagy, Zsuzsanna; Cheng, Hanyin; Stepkowski, Stanislaw M.; Kirken, Robert A.

doi:10.1007/s00005-007-0030-x

Cited by 36 publications

(28 citation statements)

References 152 publications

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“…The effect of IL-2 in cellular immunity is mainly exerted by the transcription factors STAT via IL-2R-associated JAK1 and JAK3 tyrosine kinases [7, 33, 34, 37, 38]. STAT5 is uniquely required for the expression of genes that regulate the cell cycle in peripheral T cells [39].…”

Section: Discussionmentioning

confidence: 99%

Time-Dependent Regulation of IL-2R α-Chain (CD25) Expression by TCR Signal Strength and IL-2-Induced STAT5 Signaling in Activated Human Blood T Lymphocytes

et al. 2016

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The expression of the IL-2R α-chain (IL-2Rα) is regulated at the transcriptional level via TCR- and IL-2R-signaling. The question is how to precede in time the activation signals to induce the IL-2Rα expression in native primary T cells. By comparing the effects of selective drugs on the dynamics of CD25 expression during the mitogen stimulation of human peripheral blood lymphocytes, we identified distinct Src- and JAK-dependent stages of IL-2Rα upregulation. PP2, a selective inhibitor of TCR-associated Src kinase, prevents CD25 expression at initial stages of T cell activation, prior to the cell growth. This early IL-2Rα upregulation underlies the T cell competence and the IL-2 responsiveness. We found that the activated with “weak” mitogen, the population of blood lymphocytes has some pool of competent CD25+ cells bearing a high affinity IL-2R. A distinct pattern of IL-2R signaling in resting and competent T lymphocytes has been shown. Based on the inhibitory effect of WHI-P131, a selective drug of JAK3 kinase activity, we concluded that in quiescent primary T lymphocytes, the constitutive STAT3 and the IL-2-induced prolonged STAT5 activity (assayed by tyrosine phosphorylation) is mostly JAK3-independent. In competent T cells, in the presence of IL-2 JAK3/STAT5 pathway is switched to maintain the higher and sustained IL-2Rα expression as well as cell growth and proliferation. We believe that understanding the temporal coordination of antigen- and cytokine-evoked signals in primary T cells may be useful for improving immunotherapeutic strategies.

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Section: Discussionmentioning

confidence: 99%

Time-Dependent Regulation of IL-2R α-Chain (CD25) Expression by TCR Signal Strength and IL-2-Induced STAT5 Signaling in Activated Human Blood T Lymphocytes

et al. 2016

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“…STAT4 is also an important transcription factor for T-cell signalling and differentiation. 10 Furthermore, STAT4 transduces type I IFN signals in activated monocytes. 11 CD247 encodes the T cell receptor zeta subunit, and the low expression of this receptor can result in impaired immune responses.…”

Section: Introductionmentioning

confidence: 99%

IRF5polymorphism predicts prognosis in patients with systemic sclerosis

et al. 2012

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Objective The first genome-wide association study (GWAS) of systemic sclerosis (SSc) demonstrated three non-major histocompatibility complex (MHC) susceptibility loci. The goal of this study was to investigate the impact of these gene variants on survival and severity of interstitial lung disease (ILD) in SSc. Methods The authors examined 1443 Caucasian SSc patients enrolled in the Genetics versus Environment In Scleroderma Outcome Study (GENISOS) and Scleroderma Family Registry (n = 914 – discovery cohort) and The Johns Hopkins Scleroderma Cohort (n = 529 – replication cohort). Forced vital capacity (FVC)% predicted was used as a surrogate for ILD severity. Five single nucleotide polymorphisms, IRF5 (rs10488631, rs12537284, rs4728142), STAT4 (rs3821236), CD247 (rs2056626) reached genome-wide significance in the SSc-GWAS and were examined in the current study. Results Overall, 15.5% of the patients had died over the follow-up period of 5.5 years. The IRF5 rs4728142 minor allele was predictive of longer survival in the discovery cohort (p = 0.021) and in the independent replication cohort (p = 0.047) and combined group (HR: 0.75, 95% CI 0.62 to 0.90, p = 0.002). The association of this SNP with survival was independent of age at disease onset, disease type and autoantibody profile (anticentromere and antitopoisomerase antibodies). The minor allele frequency of IRF5 rs4728142 was 49.4%. Moreover, IRF5 rs4728142 minor allele correlated with higher FVC% predicted at enrolment (p = 0.019). Finally, the IRF5 rs4728142 minor allele was associated with lower IRF5 transcript expression in patients and controls (p = 0.016 and p = 0.034, respectively), suggesting that the IRF5, rs4728142 SNP, may be functionally relevant. Conclusion An SNP in the IRF5 promoter region (rs4728142), associated with lower IRF5 transcript levels, was predictive of longer survival and milder ILD in patients with SSc.

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“…Conversely, this signaling pathway is negatively regulated by three families of proteins, suppressor of cytokine signaling, protein tyrosine phosphatases, and protein inhibitors of activated Stats (PIAS), which target different levels within the Jak/Stat signaling cascade (reviewed in Ref. 9). …”

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confidence: 99%

Forskolin-inducible cAMP Pathway Negatively Regulates T-cell Proliferation by Uncoupling the Interleukin-2 Receptor Complex

Rodriguez

Ross

Nagy

et al. 2013

Journal of Biological Chemistry

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Background: Within activated T-cells, the binding of IL-2 to its receptor initiates the Jak3/Stat5 cascade culminating in proliferation. Results: Elevated levels of cAMPi within activated T-cells suppresses proliferation by targeting multiple levels of the IL-2R cascade. Conclusion: Cross-talk occurs between cAMP/PKA and the IL-2R/Jak3/Stat5 cascade in human T-cells. Significance: Therapeutic potential exists in manipulating the described cross-talk for the treatment of various immune diseases.

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Regulation of T cell homeostasis by JAKs and STATs

Cited by 36 publications

References 152 publications

Time-Dependent Regulation of IL-2R α-Chain (CD25) Expression by TCR Signal Strength and IL-2-Induced STAT5 Signaling in Activated Human Blood T Lymphocytes

Time-Dependent Regulation of IL-2R α-Chain (CD25) Expression by TCR Signal Strength and IL-2-Induced STAT5 Signaling in Activated Human Blood T Lymphocytes

IRF5polymorphism predicts prognosis in patients with systemic sclerosis

Forskolin-inducible cAMP Pathway Negatively Regulates T-cell Proliferation by Uncoupling the Interleukin-2 Receptor Complex

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