Costimulatory strength influences the differential effects of transforming growth factor β1 for the generation of CD8+ regulatory T cells

Research output: Contribution to journalArticle

Abstract

Transforming growth factor β1 (TGFβ1) is a pleiotropic cytokine, capable of exerting diverse biologic effects. Despite its central role in multiple immune activities, the molecular signals responsible for shaping TGFβ1's immunologic properties remain poorly elucidated. We report that costimulatory strength acts as a molecular switch, which influences the differential effects of TGFβ1 on the effector and regulatory development of naïve CD8+ lymphocytes. At low costimulation, TGFβ1 inhibits proliferation of CD8+ lymphocytes and cytokine secretion, but at high costimulation the response to TGFβ1 is quite different. High costimulation combined with TGFβ1 generates CD8+CD25+ T lymphocytes which maintain robust proliferative and survival capacity in the presence of low IL-2 concentrations. Furthermore, under these conditions, a subpopulation of CD8+ T lymphocytes is generated that express Foxp3, secrete IL-10, and inhibit naïve T lymphocyte proliferation via a contact-dependent mechanism. The adoptive transfer of these CD8+CD25+Foxp3+ T cells into mice inoculated intravenously with B16F10 melanoma appears to accelerate tumor progression as reflected by an increase in the number of pulmonary metastatic tumor foci. These findings indicate that costimulatory strength may act as a molecular switch in the generation of CD8+ T cells which possess a regulatory phenotype and the capacity to reduce antitumor immune responses within tumor-bearing mice.

Original languageEnglish (US)
Pages (from-to)2937-2950
Number of pages14
JournalMolecular Immunology
Volume45
Issue number10
DOIs
StatePublished - May 1 2008

Fingerprint

Transforming Growth Factors
Regulatory T-Lymphocytes
T-Lymphocytes
Lymphocytes
Cytokines
Neoplasms
Adoptive Transfer
Interleukin-10
Interleukin-2
Melanoma
Phenotype
Lung

Keywords

  • Cell differentiation
  • Costimulation
  • Mice
  • T cells
  • Transcription factors

ASJC Scopus subject areas

  • Molecular Biology
  • Immunology

Cite this

@article{0a03737221d64930b5369403671958aa,
title = "Costimulatory strength influences the differential effects of transforming growth factor β1 for the generation of CD8+ regulatory T cells",
abstract = "Transforming growth factor β1 (TGFβ1) is a pleiotropic cytokine, capable of exerting diverse biologic effects. Despite its central role in multiple immune activities, the molecular signals responsible for shaping TGFβ1's immunologic properties remain poorly elucidated. We report that costimulatory strength acts as a molecular switch, which influences the differential effects of TGFβ1 on the effector and regulatory development of na{\"i}ve CD8+ lymphocytes. At low costimulation, TGFβ1 inhibits proliferation of CD8+ lymphocytes and cytokine secretion, but at high costimulation the response to TGFβ1 is quite different. High costimulation combined with TGFβ1 generates CD8+CD25+ T lymphocytes which maintain robust proliferative and survival capacity in the presence of low IL-2 concentrations. Furthermore, under these conditions, a subpopulation of CD8+ T lymphocytes is generated that express Foxp3, secrete IL-10, and inhibit na{\"i}ve T lymphocyte proliferation via a contact-dependent mechanism. The adoptive transfer of these CD8+CD25+Foxp3+ T cells into mice inoculated intravenously with B16F10 melanoma appears to accelerate tumor progression as reflected by an increase in the number of pulmonary metastatic tumor foci. These findings indicate that costimulatory strength may act as a molecular switch in the generation of CD8+ T cells which possess a regulatory phenotype and the capacity to reduce antitumor immune responses within tumor-bearing mice.",
keywords = "Cell differentiation, Costimulation, Mice, T cells, Transcription factors",
author = "Fan, {Timothy M} and Kranz, {David M} and Flavell, {Richard A.} and Roy, {Edward J}",
year = "2008",
month = "5",
day = "1",
doi = "10.1016/j.molimm.2008.01.019",
language = "English (US)",
volume = "45",
pages = "2937--2950",
journal = "Molecular Immunology",
issn = "0161-5890",
publisher = "Elsevier Limited",
number = "10",

}

TY - JOUR

T1 - Costimulatory strength influences the differential effects of transforming growth factor β1 for the generation of CD8+ regulatory T cells

AU - Fan, Timothy M

AU - Kranz, David M

AU - Flavell, Richard A.

AU - Roy, Edward J

PY - 2008/5/1

Y1 - 2008/5/1

N2 - Transforming growth factor β1 (TGFβ1) is a pleiotropic cytokine, capable of exerting diverse biologic effects. Despite its central role in multiple immune activities, the molecular signals responsible for shaping TGFβ1's immunologic properties remain poorly elucidated. We report that costimulatory strength acts as a molecular switch, which influences the differential effects of TGFβ1 on the effector and regulatory development of naïve CD8+ lymphocytes. At low costimulation, TGFβ1 inhibits proliferation of CD8+ lymphocytes and cytokine secretion, but at high costimulation the response to TGFβ1 is quite different. High costimulation combined with TGFβ1 generates CD8+CD25+ T lymphocytes which maintain robust proliferative and survival capacity in the presence of low IL-2 concentrations. Furthermore, under these conditions, a subpopulation of CD8+ T lymphocytes is generated that express Foxp3, secrete IL-10, and inhibit naïve T lymphocyte proliferation via a contact-dependent mechanism. The adoptive transfer of these CD8+CD25+Foxp3+ T cells into mice inoculated intravenously with B16F10 melanoma appears to accelerate tumor progression as reflected by an increase in the number of pulmonary metastatic tumor foci. These findings indicate that costimulatory strength may act as a molecular switch in the generation of CD8+ T cells which possess a regulatory phenotype and the capacity to reduce antitumor immune responses within tumor-bearing mice.

AB - Transforming growth factor β1 (TGFβ1) is a pleiotropic cytokine, capable of exerting diverse biologic effects. Despite its central role in multiple immune activities, the molecular signals responsible for shaping TGFβ1's immunologic properties remain poorly elucidated. We report that costimulatory strength acts as a molecular switch, which influences the differential effects of TGFβ1 on the effector and regulatory development of naïve CD8+ lymphocytes. At low costimulation, TGFβ1 inhibits proliferation of CD8+ lymphocytes and cytokine secretion, but at high costimulation the response to TGFβ1 is quite different. High costimulation combined with TGFβ1 generates CD8+CD25+ T lymphocytes which maintain robust proliferative and survival capacity in the presence of low IL-2 concentrations. Furthermore, under these conditions, a subpopulation of CD8+ T lymphocytes is generated that express Foxp3, secrete IL-10, and inhibit naïve T lymphocyte proliferation via a contact-dependent mechanism. The adoptive transfer of these CD8+CD25+Foxp3+ T cells into mice inoculated intravenously with B16F10 melanoma appears to accelerate tumor progression as reflected by an increase in the number of pulmonary metastatic tumor foci. These findings indicate that costimulatory strength may act as a molecular switch in the generation of CD8+ T cells which possess a regulatory phenotype and the capacity to reduce antitumor immune responses within tumor-bearing mice.

KW - Cell differentiation

KW - Costimulation

KW - Mice

KW - T cells

KW - Transcription factors

UR - http://www.scopus.com/inward/record.url?scp=41849087279&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=41849087279&partnerID=8YFLogxK

U2 - 10.1016/j.molimm.2008.01.019

DO - 10.1016/j.molimm.2008.01.019

M3 - Article

C2 - 18321576

AN - SCOPUS:41849087279

VL - 45

SP - 2937

EP - 2950

JO - Molecular Immunology

JF - Molecular Immunology

SN - 0161-5890

IS - 10

ER -