Attenuated IL-2R Signaling in CD4 Memory T Cells of T1D Subjects is Intrinsic and Dependent on Activation State

Overview

Journal Clin Immunol

Specialty Allergy & Immunology

Date 2017 Jun 25

PMID 28645874

Citations 7

Authors

Katharine Schwedhelm

Jerill Thorpe

Sara A Murray

Marc Gavin

Cate Speake

Carla Greenbaum

Karen Cerosaletti

Jane Buckner

S Alice Long

Affiliations

Soon will be listed here.

Abstract

The IL-2/IL-2R pathway is implicated in type 1 diabetes (T1D). While its role in regulatory T cell (Treg) biology is well characterized, mechanisms that influence IL-2 responses in effector T cells (Teff) are less well understood. We compared IL-2 responses in 95 healthy control and 98 T1D subjects. In T1D, low IL-2 responsiveness was most pronounced in memory Teff. Unlike Treg, CD25 expression did not influence the Teff responses. Reduced IL-2 responses in memory Teff were not rescued by resting, remained lower after activation and proliferation, and were absent in type 2 diabetes. Comparing basal IL-2 responses in resting versus activated cells, memory Teff displayed lower, but more sustained, responses to IL-2 overtime. These results suggest that T1D-associated defects in the Teff compartment are due to intrinsic factors related to activation. Evaluation of both Teff and Treg IL-2R signaling defects in T1D subjects may inform selection of therapies.

Citing Articles

Clinical and experimental treatment of type 1 diabetes.

Long S, Buckner J Clin Exp Immunol. 2022; 210(2):105-113.

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Genetic basis of defects in immune tolerance underlying the development of autoimmunity.

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The Multifactorial Progression from the Islet Autoimmunity to Type 1 Diabetes in Children.

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References

Kenefeck R, Wang C, Kapadi T, Wardzinski L, Attridge K, Clough L . Follicular helper T cell signature in type 1 diabetes. J Clin Invest. 2014; 125(1):292-303. PMC: 4382272. DOI: 10.1172/JCI76238. View

Leslie R, Palmer J, Schloot N, Lernmark A . Diabetes at the crossroads: relevance of disease classification to pathophysiology and treatment. Diabetologia. 2015; 59(1):13-20. DOI: 10.1007/s00125-015-3789-z. View

Long S, Cerosaletti K, Bollyky P, Tatum M, Shilling H, Zhang S . Defects in IL-2R signaling contribute to diminished maintenance of FOXP3 expression in CD4(+)CD25(+) regulatory T-cells of type 1 diabetic subjects. Diabetes. 2009; 59(2):407-15. PMC: 2809970. DOI: 10.2337/db09-0694. View

Long S, Walker M, Rieck M, James E, Kwok W, Sanda S . Functional islet-specific Treg can be generated from CD4+CD25- T cells of healthy and type 1 diabetic subjects. Eur J Immunol. 2009; 39(2):612-20. PMC: 2743096. DOI: 10.1002/eji.200838819. View

Rosenzwajg M, Churlaud G, Hartemann A, Klatzmann D . Interleukin 2 in the pathogenesis and therapy of type 1 diabetes. Curr Diab Rep. 2014; 14(12):553. DOI: 10.1007/s11892-014-0553-6. View

Yang J, Cutler A, Ferreira R, Reading J, Cooper N, Wallace C . Natural Variation in Interleukin-2 Sensitivity Influences Regulatory T-Cell Frequency and Function in Individuals With Long-standing Type 1 Diabetes. Diabetes. 2015; 64(11):3891-902. PMC: 4975524. DOI: 10.2337/db15-0516. View

Comte D, Karampetsou M, Kis-Toth K, Yoshida N, Bradley S, Kyttaris V . Brief Report: CD4+ T Cells From Patients With Systemic Lupus Erythematosus Respond Poorly to Exogenous Interleukin-2. Arthritis Rheumatol. 2016; 69(4):808-813. PMC: 5526072. DOI: 10.1002/art.40014. View

Walker L, von Herrath M . CD4 T cell differentiation in type 1 diabetes. Clin Exp Immunol. 2015; 183(1):16-29. PMC: 4687517. DOI: 10.1111/cei.12672. View

Choi H, Cho S, Schwartz R, Choi K . Dual effects of Sprouty1 on TCR signaling depending on the differentiation state of the T cell. J Immunol. 2006; 176(10):6034-45. DOI: 10.4049/jimmunol.176.10.6034. View

10.

Katz G, Pobezinsky L, Jeurling S, Shinzawa M, Van Laethem F, Singer A . T cell receptor stimulation impairs IL-7 receptor signaling by inducing expression of the microRNA miR-17 to target Janus kinase 1. Sci Signal. 2014; 7(340):ra83. PMC: 6679598. DOI: 10.1126/scisignal.2005221. View

11.

Hartemann A, Bensimon G, Payan C, Jacqueminet S, Bourron O, Nicolas N . Low-dose interleukin 2 in patients with type 1 diabetes: a phase 1/2 randomised, double-blind, placebo-controlled trial. Lancet Diabetes Endocrinol. 2014; 1(4):295-305. DOI: 10.1016/S2213-8587(13)70113-X. View

12.

Marwaha A, Panagiotopoulos C, Biggs C, Staiger S, Del Bel K, Hirschfeld A . Pre-diagnostic genotyping identifies T1D subjects with impaired Treg IL-2 signaling and an elevated proportion of FOXP3IL-17 cells. Genes Immun. 2017; 18(1):15-21. PMC: 5843473. DOI: 10.1038/gene.2016.44. View

13.

Chien M, Lin M, Huang S, Fu S, Hsu C, Yen B . Glucosamine Modulates T Cell Differentiation through Down-regulating N-Linked Glycosylation of CD25. J Biol Chem. 2015; 290(49):29329-44. PMC: 4705938. DOI: 10.1074/jbc.M115.674671. View

14.

Herndler-Brandstetter D, Brunner S, Weiskopf D, van Rijn R, Landgraf K, Dejaco C . Post-thymic regulation of CD5 levels in human memory T cells is inversely associated with the strength of responsiveness to interleukin-15. Hum Immunol. 2011; 72(8):627-31. PMC: 3144390. DOI: 10.1016/j.humimm.2011.03.028. View

15.

Arif S, Leete P, Nguyen V, Marks K, Mohamed Nor N, Estorninho M . Blood and islet phenotypes indicate immunological heterogeneity in type 1 diabetes. Diabetes. 2014; 63(11):3835-45. PMC: 4207393. DOI: 10.2337/db14-0365. View

16.

Long A, Buckner J . Intersection between genetic polymorphisms and immune deviation in type 1 diabetes. Curr Opin Endocrinol Diabetes Obes. 2013; 20(4):285-91. DOI: 10.1097/MED.0b013e32836285b6. View

17.

Dendrou C, Plagnol V, Fung E, Yang J, Downes K, Cooper J . Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource. Nat Genet. 2009; 41(9):1011-5. PMC: 2749506. DOI: 10.1038/ng.434. View

18.

Yu A, Snowhite I, Vendrame F, Rosenzwajg M, Klatzmann D, Pugliese A . Selective IL-2 responsiveness of regulatory T cells through multiple intrinsic mechanisms supports the use of low-dose IL-2 therapy in type 1 diabetes. Diabetes. 2015; 64(6):2172-83. DOI: 10.2337/db14-1322. View

19.

Long S, Buckner J, Greenbaum C . IL-2 therapy in type 1 diabetes: "Trials" and tribulations. Clin Immunol. 2013; 149(3):324-31. DOI: 10.1016/j.clim.2013.02.005. View

20.

Hand T, Cui W, Jung Y, Sefik E, Joshi N, Chandele A . Differential effects of STAT5 and PI3K/AKT signaling on effector and memory CD8 T-cell survival. Proc Natl Acad Sci U S A. 2010; 107(38):16601-6. PMC: 2944719. DOI: 10.1073/pnas.1003457107. View