Immune regulation by CTLA-4-relevance to autoimmune diabetes in a transgenic mouse model

Chun Jing Wang, Emily M. Schmidt, Kesley Attridge, Rupert Kenefeck, Lukasz Wardzinski, Jayne L. Chamberlain, Annelise Soulier, Louise E. Clough, Claire N. Manzotti, Parth Narendran, Lucy S.K. Walker

Research output: Contribution to journalSpecial issue

Abstract

BACKGROUND: The importance of cytotoxic T lymphocyte antigen-4 (CTLA-4) in immune regulation is unquestioned, yet a precise understanding of which cells express it, and how it mediates immune inhibitory function, is lacking. Regulatory T cells are known to constitutively express CTLA-4 intracellularly, whereas conventional T cells require activation to trigger CTLA-4 expression. However comparative analysis of CTLA-4 trafficking in regulatory and conventional subsets has not been performed.

METHODS: Here we assess CTLA-4 expression in antigen-specific conventional and regulatory cells responding to immunizing antigen in vivo and analyse the membrane trafficking of CTLA-4 using an in vitro recycling assay. We assess the expression of CTLA-4 on Treg infiltrating the pancreas in the DO11×RIP-mOVA diabetes model and the role of CTLA-4 in Treg function.

RESULTS: Regulatory T cells show an enhanced capacity to traffic CTLA-4 following stimulation compared with conventional T cells. Treg infiltrating the pancreas in DO11×RIP-mOVA mice show high expression of CTLA-4. Furthermore CTLA-4-deficient Treg fail to control diabetes in an adoptive transfer model of diabetes, even in situations where they outnumber the disease-inducing conventional T cells.

CONCLUSIONS: These data show that not only do regulatory T cells express higher levels of intracellular CTLA-4 than conventional T cells, but they also show an increased capacity to traffic CTLA-4 to the cell surface following stimulation. CTLA-4 is strongly upregulated in regulatory T cells infiltrating the target tissue in a mouse model of type 1 diabetes and expression of this protein is critical for effective regulation.

Original languageEnglish
Pages (from-to)946-950
Number of pages5
JournalDiabetes/Metabolism Research and Reviews
Volume27
Issue number8
DOIs
Publication statusPublished - Nov 2011

Fingerprint

CTLA-4 Antigen
Type 1 Diabetes Mellitus
Transgenic Mice
Regulatory T-Lymphocytes
T-Lymphocytes
Pancreas
Antigens
Adoptive Transfer
Recycling

Keywords

  • adoptive transfer
  • diabetes
  • CTLA-4 antigen
  • type 1 diabetes mellitus
  • animal disease models
  • lymphocyte activation
  • CTLA-4
  • protein transport
  • T-lymphocytes
  • regulatory T-lymphocytes
  • up-regulation
  • Treg
  • autoimmunity
  • T cells
  • immune regulation

Cite this

Wang, C. J., Schmidt, E. M., Attridge, K., Kenefeck, R., Wardzinski, L., Chamberlain, J. L., ... Walker, L. S. K. (2011). Immune regulation by CTLA-4-relevance to autoimmune diabetes in a transgenic mouse model. Diabetes/Metabolism Research and Reviews, 27(8), 946-950. https://doi.org/10.1002/dmrr.1277
Wang, Chun Jing ; Schmidt, Emily M. ; Attridge, Kesley ; Kenefeck, Rupert ; Wardzinski, Lukasz ; Chamberlain, Jayne L. ; Soulier, Annelise ; Clough, Louise E. ; Manzotti, Claire N. ; Narendran, Parth ; Walker, Lucy S.K. / Immune regulation by CTLA-4-relevance to autoimmune diabetes in a transgenic mouse model. In: Diabetes/Metabolism Research and Reviews. 2011 ; Vol. 27, No. 8. pp. 946-950.
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title = "Immune regulation by CTLA-4-relevance to autoimmune diabetes in a transgenic mouse model",
abstract = "BACKGROUND: The importance of cytotoxic T lymphocyte antigen-4 (CTLA-4) in immune regulation is unquestioned, yet a precise understanding of which cells express it, and how it mediates immune inhibitory function, is lacking. Regulatory T cells are known to constitutively express CTLA-4 intracellularly, whereas conventional T cells require activation to trigger CTLA-4 expression. However comparative analysis of CTLA-4 trafficking in regulatory and conventional subsets has not been performed.METHODS: Here we assess CTLA-4 expression in antigen-specific conventional and regulatory cells responding to immunizing antigen in vivo and analyse the membrane trafficking of CTLA-4 using an in vitro recycling assay. We assess the expression of CTLA-4 on Treg infiltrating the pancreas in the DO11×RIP-mOVA diabetes model and the role of CTLA-4 in Treg function.RESULTS: Regulatory T cells show an enhanced capacity to traffic CTLA-4 following stimulation compared with conventional T cells. Treg infiltrating the pancreas in DO11×RIP-mOVA mice show high expression of CTLA-4. Furthermore CTLA-4-deficient Treg fail to control diabetes in an adoptive transfer model of diabetes, even in situations where they outnumber the disease-inducing conventional T cells.CONCLUSIONS: These data show that not only do regulatory T cells express higher levels of intracellular CTLA-4 than conventional T cells, but they also show an increased capacity to traffic CTLA-4 to the cell surface following stimulation. CTLA-4 is strongly upregulated in regulatory T cells infiltrating the target tissue in a mouse model of type 1 diabetes and expression of this protein is critical for effective regulation.",
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Wang, CJ, Schmidt, EM, Attridge, K, Kenefeck, R, Wardzinski, L, Chamberlain, JL, Soulier, A, Clough, LE, Manzotti, CN, Narendran, P & Walker, LSK 2011, 'Immune regulation by CTLA-4-relevance to autoimmune diabetes in a transgenic mouse model', Diabetes/Metabolism Research and Reviews, vol. 27, no. 8, pp. 946-950. https://doi.org/10.1002/dmrr.1277

Immune regulation by CTLA-4-relevance to autoimmune diabetes in a transgenic mouse model. / Wang, Chun Jing; Schmidt, Emily M.; Attridge, Kesley; Kenefeck, Rupert; Wardzinski, Lukasz; Chamberlain, Jayne L.; Soulier, Annelise; Clough, Louise E.; Manzotti, Claire N.; Narendran, Parth; Walker, Lucy S.K.

In: Diabetes/Metabolism Research and Reviews, Vol. 27, No. 8, 11.2011, p. 946-950.

Research output: Contribution to journalSpecial issue

TY - JOUR

T1 - Immune regulation by CTLA-4-relevance to autoimmune diabetes in a transgenic mouse model

AU - Wang, Chun Jing

AU - Schmidt, Emily M.

AU - Attridge, Kesley

AU - Kenefeck, Rupert

AU - Wardzinski, Lukasz

AU - Chamberlain, Jayne L.

AU - Soulier, Annelise

AU - Clough, Louise E.

AU - Manzotti, Claire N.

AU - Narendran, Parth

AU - Walker, Lucy S.K.

N1 - Copyright © 2011 John Wiley & Sons, Ltd.

PY - 2011/11

Y1 - 2011/11

N2 - BACKGROUND: The importance of cytotoxic T lymphocyte antigen-4 (CTLA-4) in immune regulation is unquestioned, yet a precise understanding of which cells express it, and how it mediates immune inhibitory function, is lacking. Regulatory T cells are known to constitutively express CTLA-4 intracellularly, whereas conventional T cells require activation to trigger CTLA-4 expression. However comparative analysis of CTLA-4 trafficking in regulatory and conventional subsets has not been performed.METHODS: Here we assess CTLA-4 expression in antigen-specific conventional and regulatory cells responding to immunizing antigen in vivo and analyse the membrane trafficking of CTLA-4 using an in vitro recycling assay. We assess the expression of CTLA-4 on Treg infiltrating the pancreas in the DO11×RIP-mOVA diabetes model and the role of CTLA-4 in Treg function.RESULTS: Regulatory T cells show an enhanced capacity to traffic CTLA-4 following stimulation compared with conventional T cells. Treg infiltrating the pancreas in DO11×RIP-mOVA mice show high expression of CTLA-4. Furthermore CTLA-4-deficient Treg fail to control diabetes in an adoptive transfer model of diabetes, even in situations where they outnumber the disease-inducing conventional T cells.CONCLUSIONS: These data show that not only do regulatory T cells express higher levels of intracellular CTLA-4 than conventional T cells, but they also show an increased capacity to traffic CTLA-4 to the cell surface following stimulation. CTLA-4 is strongly upregulated in regulatory T cells infiltrating the target tissue in a mouse model of type 1 diabetes and expression of this protein is critical for effective regulation.

AB - BACKGROUND: The importance of cytotoxic T lymphocyte antigen-4 (CTLA-4) in immune regulation is unquestioned, yet a precise understanding of which cells express it, and how it mediates immune inhibitory function, is lacking. Regulatory T cells are known to constitutively express CTLA-4 intracellularly, whereas conventional T cells require activation to trigger CTLA-4 expression. However comparative analysis of CTLA-4 trafficking in regulatory and conventional subsets has not been performed.METHODS: Here we assess CTLA-4 expression in antigen-specific conventional and regulatory cells responding to immunizing antigen in vivo and analyse the membrane trafficking of CTLA-4 using an in vitro recycling assay. We assess the expression of CTLA-4 on Treg infiltrating the pancreas in the DO11×RIP-mOVA diabetes model and the role of CTLA-4 in Treg function.RESULTS: Regulatory T cells show an enhanced capacity to traffic CTLA-4 following stimulation compared with conventional T cells. Treg infiltrating the pancreas in DO11×RIP-mOVA mice show high expression of CTLA-4. Furthermore CTLA-4-deficient Treg fail to control diabetes in an adoptive transfer model of diabetes, even in situations where they outnumber the disease-inducing conventional T cells.CONCLUSIONS: These data show that not only do regulatory T cells express higher levels of intracellular CTLA-4 than conventional T cells, but they also show an increased capacity to traffic CTLA-4 to the cell surface following stimulation. CTLA-4 is strongly upregulated in regulatory T cells infiltrating the target tissue in a mouse model of type 1 diabetes and expression of this protein is critical for effective regulation.

KW - adoptive transfer

KW - diabetes

KW - CTLA-4 antigen

KW - type 1 diabetes mellitus

KW - animal disease models

KW - lymphocyte activation

KW - CTLA-4

KW - protein transport

KW - T-lymphocytes

KW - regulatory T-lymphocytes

KW - up-regulation

KW - Treg

KW - autoimmunity

KW - T cells

KW - immune regulation

UR - http://onlinelibrary.wiley.com/doi/10.1002/dmrr.1277/abstract

U2 - 10.1002/dmrr.1277

DO - 10.1002/dmrr.1277

M3 - Special issue

C2 - 22069290

VL - 27

SP - 946

EP - 950

JO - Diabetes/Metabolism Research and Reviews

JF - Diabetes/Metabolism Research and Reviews

SN - 1520-7552

IS - 8

ER -

Wang CJ, Schmidt EM, Attridge K, Kenefeck R, Wardzinski L, Chamberlain JL et al. Immune regulation by CTLA-4-relevance to autoimmune diabetes in a transgenic mouse model. Diabetes/Metabolism Research and Reviews. 2011 Nov;27(8):946-950. https://doi.org/10.1002/dmrr.1277