Top

Published in:

Open Access 01-12-2018 | Research

CISH promoter polymorphism effects on T cell cytokine receptor signaling and type 1 diabetes susceptibility

Authors: Julia Seyfarth, Heinz Ahlert, Joachim Rosenbauer, Christina Baechle, Michael Roden, Reinhard W. Holl, Ertan Mayatepek, Thomas Meissner, Marc Jacobsen

Published in: Molecular and Cellular Pediatrics | Issue 1/2018

Abstract

Background

Impaired regulatory T cell immunity plays a central role in the development of type 1 diabetes (T1D). Interleukin-2 receptor (IL-2R) signaling is essential for regulatory T cells (T_REG), and cytokine-inducible SH2-containing protein (CIS) regulates IL-2R signaling as a feedback inhibitor. Previous studies identified association of CISH promoter region single nucleotide polymorphisms (SNPs) with susceptibility to infectious diseases.

Methods

Here we analyzed allele frequencies of three CISH SNPs (i.e., rs809451, rs414171, rs2239751) in a study of T1D patients (n = 260, onset age < 5 years, duration > 10 years). Minor allele frequencies were compared to a control cohort of the 1000 Genomes Project. Assigned haplotypes were determined for effects on T1D manifestation and severity. Finally, the CISH haplotype influence on cytokine signaling and function was explored in T cells from healthy donors.

Results

We detected similar minor allele frequencies between T1D patients and the control cohort. T1D onset age, residual serum C-peptide level, and insulin requirement were comparable between different haplotypes. Only minor differences between the haplotypes were found for in vitro cytokine (i.e., IL-2, IL-7)-induced CIS mRNA expression. STAT5 phosphorylation was induced by IL-2 or IL-7, but no differences were found between the haplotypes. T_REG purified from healthy donors with the two most common haplotypes showed similar capacity to inhibit heterologous effector T cells.

Conclusions

This study provides no evidence for an association of CISH promoter SNPs with susceptibility to T1D or severity of disease. In contrast to previous studies, no influence of different haplotypes on CIS mRNA expression or T cell-mediated functions was found.

Available only for authorised users

Brusko TM, Wasserfall CH, Clare-Salzler MJ, Schatz DA, Atkinson MA (2005) Functional defects and the influence of age on the frequency of CD4+ CD25+ T-cells in type 1 diabetes. Diabetes 54(5):1407–1414 PubMed PMID: 15855327CrossRefPubMed

Lindley S, Dayan CM, Bishop A, Roep BO, Peakman M, Tree TI (2005) Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. Diabetes 54(1):92–99 PubMed PMID: 15616015CrossRefPubMed

Lowe CE, Cooper JD, Brusko T, Walker NM, Smyth DJ, Bailey R et al (2007) Large-scale genetic fine mapping and genotype-phenotype associations implicate polymorphism in the IL2RA region in type 1 diabetes. Nat Genet 39(9):1074–1082. https://doi.org/10.1038/ng2102 PubMed PMID: 17676041CrossRefPubMed

Dendrou CA, Plagnol V, Fung E, Yang JH, Downes K, Cooper JD et al (2009) Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource. Nat Genet 41(9):1011–1015. https://doi.org/10.1038/ng.434 PubMed PMID: 19701192; PubMed Central PMCID: PMCPMC2749506CrossRefPubMedPubMedCentral

Chistiakov DA, Voronova NV, Chistiakov PA (2008) The crucial role of IL-2/IL-2RA-mediated immune regulation in the pathogenesis of type 1 diabetes, an evidence coming from genetic and animal model studies. Immunol Lett 118(1):1–5. https://doi.org/10.1016/j.imlet.2008.03.002 PubMed PMID: 18417224CrossRefPubMed

Ilangumaran S, Ramanathan S, Rottapel R (2004) Regulation of the immune system by SOCS family adaptor proteins. Semin Immunol 16(6):351–365. https://doi.org/10.1016/j.smim.2004.08.015 PubMed PMID: 15541651CrossRefPubMed

Li S, Chen S, Xu X, Sundstedt A, Paulsson KM, Anderson P et al (2000) Cytokine-induced Src homology 2 protein (CIS) promotes T cell receptor-mediated proliferation and prolongs survival of activated T cells. J Exp Med 191(6):985–994 Epub 2000/03/23. PubMed PMID: 10727460; PubMed Central PMCID: PMC2193118CrossRefPubMedPubMedCentral

Matsumoto A, Masuhara M, Mitsui K, Yokouchi M, Ohtsubo M, Misawa H et al (1997) CIS, a cytokine inducible SH2 protein, is a target of the JAK-STAT5 pathway and modulates STAT5 activation. Blood 89(9):3148–3154 PubMed PMID: 9129017PubMed

Aman MJ, Migone TS, Sasaki A, Ascherman DP, Zhu M, Soldaini E et al (1999) CIS associates with the interleukin-2 receptor beta chain and inhibits interleukin-2-dependent signaling. J Biol Chem 274(42):30266–30272 Epub 1999/10/09. PubMed PMID: 10514520CrossRefPubMed

10.

Matsumoto A, Seki Y, Kubo M, Ohtsuka S, Suzuki A, Hayashi I et al (1999) Suppression of STAT5 functions in liver, mammary glands, and T cells in cytokine-inducible SH2-containing protein 1 transgenic mice. Mol Cell Biol 19(9):6396–6407 Epub 1999/08/24. PubMed PMID: 10454585; PubMed Central PMCID: PMC84609CrossRefPubMedPubMedCentral

11.

Khor CC, Vannberg FO, Chapman SJ, Guo H, Wong SH, Walley AJ et al (2010) CISH and susceptibility to infectious diseases. N Engl J Med 362(22):2092–2101. https://doi.org/10.1056/NEJMoa0905606 Epub 2010/05/21. PubMed PMID: 20484391; PubMed Central PMCID: PMC3646238CrossRefPubMedPubMedCentral

12.

Palmer DC, Guittard GC, Franco Z, Crompton JG, Eil RL, Patel SJ et al (2015) CISH actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance. J Exp Med 212(12):2095–2113. https://doi.org/10.1084/jem.20150304 PubMed PMID: 26527801; PubMed Central PMCID: PMCPMC4647263CrossRefPubMedPubMedCentral

13.

Yang XO, Zhang H, Kim BS, Niu X, Peng J, Chen Y et al (2013) The signaling suppressor CIS controls proallergic T cell development and allergic airway inflammation. Nat Immunol 14(7):732–740. https://doi.org/10.1038/ni.2633 Epub 2013/06/04. PubMed PMID: 23727894CrossRefPubMedPubMedCentral

14.

Zhao L, Chu H, Xu X, Yue J, Li H, Wang M (2013) Association between single-nucleotide polymorphism in CISH gene and susceptibility to tuberculosis in Chinese Han population. Cell Biochem Biophys. https://doi.org/10.1007/s12013-013-9733-2 Epub 2013/08/21. PubMed PMID: 23949851

15.

Ji LD, Xu WN, Chai PF, Zheng W, Qian HX, Xu J (2014) Polymorphisms in the CISH gene are associated with susceptibility to tuberculosis in the Chinese Han population. Infect Genet Evol 28:240–244. https://doi.org/10.1016/j.meegid.2014.10.006 PubMed PMID: 25460819CrossRefPubMed

16.

Sun L, Jin YQ, Shen C, Qi H, Chu P, Yin QQ et al (2014) Genetic contribution of CISH promoter polymorphisms to susceptibility to tuberculosis in Chinese children. PLoS One 9(3):e92020. https://doi.org/10.1371/journal.pone.0092020 PubMed PMID: 24632804; PubMed Central PMCID: PMCPMC3954833CrossRefPubMedPubMedCentral

17.

Genomes Project C, Abecasis GR, Altshuler D, Auton A, Brooks LD, Durbin RM et al (2010) A map of human genome variation from population-scale sequencing. Nature 467(7319):1061–1073. https://doi.org/10.1038/nature09534 PubMed PMID: 20981092; PubMed Central PMCID: PMCPMC3042601CrossRef

18.

Reinauer C, Rosenbauer J, Bachle C, Herder C, Roden M, Ellard S et al (2017) The clinical course of patients with preschool manifestation of type 1 diabetes is independent of the HLA DR-DQ genotype. Genes (Basel) 8(5). https://doi.org/10.3390/genes8050146 PubMed PMID: 28534863; PubMed Central PMCID: PMCPMC5448020

19.

Hoenig JM, Heisey DM (2001) The abuse of power: the pervasive fallacy of power calculations for data analysis. Am Stat 55(1):19–24. https://doi.org/10.1198/000313001300339897 PubMed PMID: WOS:000166827400005CrossRef

20.

Jacobsen M, Repsilber D, Kleinsteuber K, Gutschmidt A, Schommer-Leitner S, Black G et al (2011) Suppressor of cytokine signaling-3 is affected in T-cells from tuberculosis TB patients. Clin Microbiol Infect 17(9):1323–1331. https://doi.org/10.1111/j.1469-0691.2010.03326.x PubMed PMID: 20673263CrossRefPubMed

21.

Cabrera SM, Rigby MR, Mirmira RG (2012) Targeting regulatory T cells in the treatment of type 1 diabetes mellitus. Curr Mol Med 12(10):1261–1272 PubMed PMID: 22709273; PubMed Central PMCID: PMCPMC3709459CrossRefPubMedPubMedCentral

22.

Zhang X, Ing S, Fraser A, Chen M, Khan O, Zakem J et al (2013) Follicular helper T cells: new insights into mechanisms of autoimmune diseases. Ochsner J 13(1):131–139 PubMed PMID: 23531878; PubMed Central PMCID: PMCPMC3603176PubMedPubMedCentral

23.

Gupta S, Cerosaletti K, Long SA (2014) Renegade homeostatic cytokine responses in T1D: drivers of regulatory/effector T cell imbalance. Clin Immunol 151(2):146–154. https://doi.org/10.1016/j.clim.2014.02.007 Epub 2014/03/01. PubMed PMID: 24576418CrossRefPubMed

24.

Delconte RB, Kolesnik TB, Dagley LF, Rautela J, Shi W, Putz EM et al (2016) CIS is a potent checkpoint in NK cell-mediated tumor immunity. Nat Immunol 17(7):816–824. https://doi.org/10.1038/ni.3470 PubMed PMID: 27213690CrossRefPubMed

Title: CISH promoter polymorphism effects on T cell cytokine receptor signaling and type 1 diabetes susceptibility
Authors: Julia Seyfarth
Heinz Ahlert
Joachim Rosenbauer
Christina Baechle
Michael Roden
Reinhard W. Holl
Ertan Mayatepek
Thomas Meissner
Marc Jacobsen
Publication date: 01-12-2018
Publisher: Springer Berlin Heidelberg
Published in: Molecular and Cellular Pediatrics / Issue 1/2018
Electronic ISSN: 2194-7791
DOI: https://doi.org/10.1186/s40348-018-0080-7

At a glance: The STEP trials

Springer Medicine

CISH promoter polymorphism effects on T cell cytokine receptor signaling and type 1 diabetes susceptibility

Abstract

Background

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2018

Preserved in vitro immunoreactivity in children receiving long-term immunosuppressive therapy due to inflammatory bowel disease or autoimmune hepatitis

Anti-inflammatory monocytes—interplay of innate and adaptive immunity

Gene correction of HBB mutations in CD34+ hematopoietic stem cells using Cas9 mRNA and ssODN donors

Precision medicine in pediatric oncology

The role of S100 proteins in the pathogenesis and monitoring of autoinflammatory diseases

Chemotherapy and the pediatric brain