Modulation of cord blood CD8+ T-cell effector differentiation by TGF-β1 and 4-1BB costimulation

Young June Kim, Teresa M. Stringfield, Yan Chen, Hal Broxmeyer

Research output: Contribution to journalArticle

21 Citations (Scopus)

Abstract

Transforming growth factor-β1 (TGF-β1), an immunosuppressive cytokine, inhibits cytotoxic T cell (CTL) immune responses. In contrast, 4-1BB (CD137), a costimulatory molecule in the tumor necrosis factor (TNF) receptor family, amplifies CTL-mediated antitumor immune responses. We investigated whether TGF-β1 responses could be reversed by 4-1BB costimulation during in vitro differentiation of naive CD8+ T cells into effector CTL cells. TGF-β1 potently suppressed CTL differentiation of human cord blood naive CD8+ T cells as determined by reduced induction of characteristic phenotypes of effector cells and cytotoxic activity. TGF-β1-mediated suppression of CTL differentiation was abrogated by 4-1BB costimulation but not by CD28 or another member in the TNF receptor family, CD30. 4-1BB costimulation suppressed Smad2 phosphorylation induced by TGF-β1, suggesting that 4-1BB effects were at the level of TGF-β1 signaling. 4-1BB effects on the TGF-β1-mediated suppression were enhanced by interleukin 12 (IL-12) but counteracted by IL-4; 4-1BB expression was up- or down-regulated, respectively, by IL-12 and IL-4. IL-4 was more dominant than IL-12 when both cytokines were present during 4-1BB costimulation in the presence of TGF-β1. This indicates critical roles for IL-4 and IL-12 in regulating 4-1BB effects on TGF-β1-mediated suppression.

Original languageEnglish
Pages (from-to)274-281
Number of pages8
JournalBlood
Volume105
Issue number1
DOIs
StatePublished - Jan 1 2005

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T-cells
Transforming Growth Factors
Fetal Blood
Cell Differentiation
Blood
Modulation
T-Lymphocytes
Interleukin-12
Interleukin-4
Tumor Necrosis Factor Receptors
Cytokines
Phosphorylation
Immunosuppressive Agents
Phenotype
Molecules

ASJC Scopus subject areas

  • Hematology

Cite this

Modulation of cord blood CD8+ T-cell effector differentiation by TGF-β1 and 4-1BB costimulation. / Kim, Young June; Stringfield, Teresa M.; Chen, Yan; Broxmeyer, Hal.

In: Blood, Vol. 105, No. 1, 01.01.2005, p. 274-281.

Research output: Contribution to journalArticle

Kim, Young June ; Stringfield, Teresa M. ; Chen, Yan ; Broxmeyer, Hal. / Modulation of cord blood CD8+ T-cell effector differentiation by TGF-β1 and 4-1BB costimulation. In: Blood. 2005 ; Vol. 105, No. 1. pp. 274-281.
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