Homeostasis and function of regulatory T cells (Tregs) in vivo

lessons from TCR-transgenic Tregs

Kesley Attridge, Lucy S.K. Walker

Research output: Contribution to journalReview article

Abstract

The identification of CD25 and subsequently Forkhead box protein 3 (Foxp3) as markers for regulatory T cells (Tregs) has revolutionized our ability to explore this population experimentally. In a similar vein, our understanding of antigen-specific Treg responses in vivo owes much to the fortuitous generation of T-cell receptor (TCR)-transgenic Tregs. This has permitted tracking of Tregs with a defined specificity in vivo, facilitating analysis of how encounter with cognate antigen shapes Treg homeostasis and function. Here, we review the key lessons learned from a decade of analysis of TCR-transgenic Tregs and set this in the broader context of general progress in the field. Use of TCR-transgenic Tregs has led to an appreciation that Tregs are a highly dynamic proliferative population in vivo, rather than an anergic population as they were initially portrayed. It is now clear that Treg homeostasis is positively regulated by encounter with self-antigen expressed on peripheral tissues, which is likely to be relevant to the phenomenon of peripheral repertoire reshaping that has been described for Tregs and the observation that the Treg TCR specificities vary by anatomical location. Substantial evidence has also accumulated to support the role of CD28 costimulation and interleukin-2 in Treg homeostasis. The availability of TCR-transgenic Tregs has enabled analysis of Treg populations that are sufficient or deficient in particular genes, without the comparison being confounded by repertoire alterations. This approach has yielded insights into genes required for Treg function in vivo, with particular progress being made on the role of ctla-4 in this context. As the prospect of manipulating Treg populations in the clinic becomes reality, a full appreciation of the rules governing their homeostasis will prove increasingly important.

Original languageEnglish
Pages (from-to)23-39
Number of pages17
JournalImmunological Reviews
Volume259
Issue number1
Early online date9 Apr 2014
DOIs
Publication statusPublished - May 2014

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Regulatory T-Lymphocytes
T-Cell Antigen Receptor
Homeostasis
Population
T-Cell Antigen Receptor Specificity
Forkhead Transcription Factors
Antigens
Autoantigens
Population Dynamics
Genes
Interleukin-2
Veins

Bibliographical note

© 2014 The Authors. Immunological Reviews Published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Keywords

  • antigen-mediated clonal selection
  • antigen
  • homeostasis
  • T-cell
  • immune tolerance
  • lymphocyte activation
  • receptors
  • signal transduction
  • regulatory T-lymphocytes
  • thymus gland
  • immune regulation
  • Tregs
  • tolerance
  • TCR-transgenic
  • Treg proliferation
  • Treg function

Cite this

Attridge, Kesley ; Walker, Lucy S.K. / Homeostasis and function of regulatory T cells (Tregs) in vivo : lessons from TCR-transgenic Tregs. In: Immunological Reviews. 2014 ; Vol. 259, No. 1. pp. 23-39.
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Attridge, K & Walker, LSK 2014, 'Homeostasis and function of regulatory T cells (Tregs) in vivo: lessons from TCR-transgenic Tregs', Immunological Reviews, vol. 259, no. 1, pp. 23-39. https://doi.org/10.1111/imr.12165

Homeostasis and function of regulatory T cells (Tregs) in vivo : lessons from TCR-transgenic Tregs. / Attridge, Kesley; Walker, Lucy S.K.

In: Immunological Reviews, Vol. 259, No. 1, 05.2014, p. 23-39.

Research output: Contribution to journalReview article

TY - JOUR

T1 - Homeostasis and function of regulatory T cells (Tregs) in vivo

T2 - lessons from TCR-transgenic Tregs

AU - Attridge, Kesley

AU - Walker, Lucy S.K.

N1 - © 2014 The Authors. Immunological Reviews Published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

PY - 2014/5

Y1 - 2014/5

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AB - The identification of CD25 and subsequently Forkhead box protein 3 (Foxp3) as markers for regulatory T cells (Tregs) has revolutionized our ability to explore this population experimentally. In a similar vein, our understanding of antigen-specific Treg responses in vivo owes much to the fortuitous generation of T-cell receptor (TCR)-transgenic Tregs. This has permitted tracking of Tregs with a defined specificity in vivo, facilitating analysis of how encounter with cognate antigen shapes Treg homeostasis and function. Here, we review the key lessons learned from a decade of analysis of TCR-transgenic Tregs and set this in the broader context of general progress in the field. Use of TCR-transgenic Tregs has led to an appreciation that Tregs are a highly dynamic proliferative population in vivo, rather than an anergic population as they were initially portrayed. It is now clear that Treg homeostasis is positively regulated by encounter with self-antigen expressed on peripheral tissues, which is likely to be relevant to the phenomenon of peripheral repertoire reshaping that has been described for Tregs and the observation that the Treg TCR specificities vary by anatomical location. Substantial evidence has also accumulated to support the role of CD28 costimulation and interleukin-2 in Treg homeostasis. The availability of TCR-transgenic Tregs has enabled analysis of Treg populations that are sufficient or deficient in particular genes, without the comparison being confounded by repertoire alterations. This approach has yielded insights into genes required for Treg function in vivo, with particular progress being made on the role of ctla-4 in this context. As the prospect of manipulating Treg populations in the clinic becomes reality, a full appreciation of the rules governing their homeostasis will prove increasingly important.

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KW - antigen

KW - homeostasis

KW - T-cell

KW - immune tolerance

KW - lymphocyte activation

KW - receptors

KW - signal transduction

KW - regulatory T-lymphocytes

KW - thymus gland

KW - immune regulation

KW - Tregs

KW - tolerance

KW - TCR-transgenic

KW - Treg proliferation

KW - Treg function

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DO - 10.1111/imr.12165

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