Journal
IMMUNOBIOLOGY
Volume 217, Issue 1, Pages 74-82Publisher
ELSEVIER GMBH, URBAN & FISCHER VERLAG
DOI: 10.1016/j.imbio.2011.07.032
Keywords
Cytokines; Regulatory T cells; T cell differentiation; T cell subsets; Th17 cells
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Funding
- Grant Agency of the Academy of Sciences [KAN200520804]
- Ministry of Education of the Czech Republic [1M0506, MSM0021620858]
- Grant Agency of the Czech Republic [P304/11/0653, P301/11/1568, 310/08/H077]
- Academy of Sciences of the Czech Republic [AVOZ50520514]
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The development and differentiation of T helper (Th) cell subsets is a highly plastic process which is strictly regulated by cytokines. Here we show that the transforming growth factor beta (TGF-beta)-dependent differentiation programs are negatively regulated by interleukin-12 (IL-12). The development of TGF-beta-induced regulatory T cells (iTregs) or TGF-beta/IL-6 activated Th17 cells from purified mouse CD4(+)CD25(-) T cells, stimulated with monoclonal antibody anti-CD3, was abrogated in the presence of IL-12 and a different developmental program was established. On the molecular level, IL-12 inhibited the expression of the lineage specific transcription factors Foxp3 and ROR gamma t in developing Tregs and Th17 cells, respectively. Moreover, IL-12 was able to alter the development of iTregs and Th17 cells even when added to the differentiating cells after 48 h of the culture. The cells activated in the presence of TGF-beta and IL-12 had an increased expression of the Th1 transcription factor T-bet, produced Th1 cytokines interferon gamma and IL-2 and expressed IL-18 receptor and C-C chemokine receptor type 5 which are the phenotypic markers characteristic for Th1 cells. Furthermore, the cells activated in the presence of both TGF-beta and IL-12, and not of TGF-beta only, stimulated macrophages to produce nitric oxide. Altogether, these results indicate that IL-12 is a superior cytokine that has the ability to skew the already ongoing TGF-beta-dependent iTreg or Th17 developmental program into Th1-like direction. (C) 2011 Elsevier GmbH. All rights reserved.
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