Reduced interleukin-2 responsiveness impairs the ability of Treg cells to compete for IL-2 in nonobese diabetic mice

James, Cini R., Buckle, Irina, Muscate, Franziska, Otsuka, Masayuki, Nakao, Mari, Oon, Jack S. H., Steptoe, Raymond J., Thomas, Ranjeny and Hamilton-Williams, Emma E. (2016) Reduced interleukin-2 responsiveness impairs the ability of Treg cells to compete for IL-2 in nonobese diabetic mice. Immunology and Cell Biology, 94 5: 509-519. doi:10.1038/icb.2016.7


Author James, Cini R.
Buckle, Irina
Muscate, Franziska
Otsuka, Masayuki
Nakao, Mari
Oon, Jack S. H.
Steptoe, Raymond J.
Thomas, Ranjeny
Hamilton-Williams, Emma E.
Title Reduced interleukin-2 responsiveness impairs the ability of Treg cells to compete for IL-2 in nonobese diabetic mice
Formatted title
Reduced interleukin-2 responsiveness impairs the ability of Treg cells to compete for IL-2 in nonobese diabetic mice
Journal name Immunology and Cell Biology   Check publisher's open access policy
ISSN 1440-1711
0818-9641
Publication date 2016-05-01
Year available 2016
Sub-type Article (original research)
DOI 10.1038/icb.2016.7
Open Access Status Not Open Access
Volume 94
Issue 5
Start page 509
End page 519
Total pages 11
Place of publication London, United Kingdom
Publisher Nature Publishing Group
Language eng
Subject 2403 Immunology
1307 Cell Biology
Abstract Enhancement of regulatory T cell (T reg cell) frequency and function is the goal of many therapeutic strategies aimed at treating type 1 diabetes (T1D). The interleukin-2 (IL-2) pathway, which has been strongly implicated in T1D susceptibility in both humans and mice, is a master regulator of T reg cell homeostasis and function. We investigated how IL-2 pathway defects impact T reg cells in T1D-susceptible nonobese diabetic (NOD) mice in comparison with protected C57BL/6 and NOD congenic mice. NOD T reg cells were reduced in frequency specifically in the lymph nodes and expressed lower levels of CD25 and CD39/CD73 immunosuppressive molecules. In the spleen and blood, T reg cell frequency was preserved through expansion of CD25 low, effector phenotype T reg cells. Reduced CD25 expression led to decreased IL-2 signaling in NOD T reg cells. In vivo, treatment with IL-2-anti-IL-2 antibody complexes led to effective upregulation of suppressive molecules on NOD T reg cells in the spleen and blood, but had reduced efficacy on lymph node T reg cells. In contrast, NOD CD8 + and CD4 effector T cells were not impaired in their response to IL-2 therapy. We conclude that NOD T reg cells have an impaired responsiveness to IL-2 that reduces their ability to compete for a limited supply of IL-2.
Formatted abstract
Enhancement of regulatory T cell (Treg cell) frequency and function is the goal of many therapeutic strategies aimed at treating type 1 diabetes (T1D). The interleukin-2 (IL-2) pathway, which has been strongly implicated in T1D susceptibility in both humans and mice, is a master regulator of Treg cell homeostasis and function. We investigated how IL-2 pathway defects impact Treg cells in T1D-susceptible nonobese diabetic (NOD) mice in comparison with protected C57BL/6 and NOD congenic mice. NOD Treg cells were reduced in frequency specifically in the lymph nodes and expressed lower levels of CD25 and CD39/CD73 immunosuppressive molecules. In the spleen and blood, Treg cell frequency was preserved through expansion of CD25low, effector phenotype Treg cells. Reduced CD25 expression led to decreased IL-2 signaling in NOD Treg cells. In vivo, treatment with IL-2–anti-IL-2 antibody complexes led to effective upregulation of suppressive molecules on NOD Treg cells in the spleen and blood, but had reduced efficacy on lymph node Treg cells. In contrast, NOD CD8+ and CD4+ effector T cells were not impaired in their response to IL-2 therapy. We conclude that NOD Treg cells have an impaired responsiveness to IL-2 that reduces their ability to compete for a limited supply of IL-2.
Keyword Cell Biology
Immunology
Cell Biology
Immunology
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID APP1021324
Institutional Status UQ
Additional Notes Published May/June 2016

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
UQ Diamantina Institute Publications
 
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