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, 448 (7152), 484-487

IL-21 Initiates an Alternative Pathway to Induce Proinflammatory T(H)17 Cells

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IL-21 Initiates an Alternative Pathway to Induce Proinflammatory T(H)17 Cells

Thomas Korn et al. Nature.

Abstract

On activation, naive T cells differentiate into effector T-cell subsets with specific cytokine phenotypes and specialized effector functions. Recently a subset of T cells, distinct from T helper (T(H))1 and T(H)2 cells, producing interleukin (IL)-17 (T(H)17) was defined and seems to have a crucial role in mediating autoimmunity and inducing tissue inflammation. We and others have shown that transforming growth factor (TGF)-beta and IL-6 together induce the differentiation of T(H)17 cells, in which IL-6 has a pivotal function in dictating whether T cells differentiate into Foxp3+ regulatory T cells (T(reg) cells) or T(H)17 cells. Whereas TGF-beta induces Foxp3 and generates T(reg) cells, IL-6 inhibits the generation of T(reg) cells and induces the production of IL-17, suggesting a reciprocal developmental pathway for T(H)17 and T(reg) cells. Here we show that IL-6-deficient (Il6-/-) mice do not develop a T(H)17 response and their peripheral repertoire is dominated by Foxp3+ T(reg) cells. However, deletion of T(reg) cells leads to the reappearance of T(H)17 cells in Il6-/- mice, suggesting an additional pathway by which T(H)17 cells might be generated in vivo. We show that an IL-2 cytokine family member, IL-21, cooperates with TGF-beta to induce T(H)17 cells in naive Il6-/- T cells and that IL-21-receptor-deficient T cells are defective in generating a T(H)17 response.

Figures

Figure 1
Figure 1. In the absence of IL-6, antigen-specific Foxp31 Treg cells expand at the expense of effector T cells (Teff cells)in vivo
Foxp3gfp.KI (filled circles)or Il6−/− × Foxp3gfp.KI (Il6−/−; open triangles) mice were immunized with MOG35–55/CFA. a, Draining lymph-node cells were tested for MOG-specific proliferation and IL-17 production (means ± s.d. for triplicate determinations). b, The fraction of Foxp3/GFP+ T cells was determined ex vivo by flow cytometry (asterisk, P < 6 × 10−7; t-test). WT, wild type. c, d, Lymphnode cells (c) and splenocytes (d) from MOG35–55/CFA-immunized WT and Il6−/− mice were cultured for four days in the presence of MOG35–55 and stained with a MOG35–55/IAb tetramer. The ratios of antigen-specific Treg cells (MOG tetramer+CD4+Foxp3+) to Teff (MOG tetramer+CD4+Foxp3) cells are presented (asterisk, P < 0.0003; two asterisks, P < 0.05; t-test).
Figure 2
Figure 2. Depletion of Treg cells in Il6−/− mice restores the development of TH17 cells and susceptibility to EAE
Il6−/− × Foxp3gfp.KI mice were treated with antibody against CD25 to deplete Treg cells or with a control immunoglobulin (rat IgG1) and then immunized with MOG35–55/CFA. a, b, Clinical EAE scores (means and s.e.m.) (a) and linear regression analysis in acute (b, top) and chronic (b, bottom) stages of the disease for wild-type (WT), control Il6−/− and Treg-depleted Il6−/− mice (n.s., not significant). c, Lymph-node (LN) cells and mononuclear cells from the central nervous system (CNS) were recovered on days 6, 14–17 (peak disease) and 29 (recovery) and stained for CD4 and intracellular IL-17 and IFN-γ. The numbers in the quadrants show percentages. d, Splenocytes (day 10) were stimulated with MOG35–55in vitro. Culture supernatants were collected after 48 h, and IL-17 and IFN-γ concentrations were determined. Filled circles, WT (IgG); open triangles, Il6−/− (IgG); open circles, Il6−/− (anti-CD25).
Figure 3
Figure 3. Inhibition of induction of Treg cells and generation of TH17 cells by IL-21
CD4+CD62LhiFoxp3/GFP T cells from Foxp3gfp.KI mice were stimulated with anti-CD3 and anti-CD28 for three days in the presence of the indicated cytokines. a, The expression of Foxp3/GFP was measured and the fraction of Foxp3+ cells induced by TGF-β was normalized to 100%. b, Individual histograms showing Foxp3/GFP expression. The numbers above the histogram regions (horizontal lines) represent the percentages of Foxp3/GFP+ cells. c, IL-17 production in these cultures after 48 h as measured by ELISA. d, ROR-γt expression as determined by quantitative RT–PCR in naive 2D2 (ref. 30) T cells activated for 48 h with anti-CD3 in the presence of irradiated syngeneic antigen-presenting cells and the indicated cytokines. ROR-γt expression is shown as mean and s.e.m. for duplicate determinations, relative to β-actin.
Figure 4
Figure 4. IL-21-driven TH17 differentiation is independent of IL-6
Naive (a, b), total (c) or CD44+CD4+ T cells (d, e) were cultured with anti-CD3 plus corresponding irradiated antigen-presenting cells (a, c) or anti-CD3 plus anti-CD28 (b, d, e) and the indicated cytokines. a, c, Percentages of IL-17+ and IFN-γ+ cells in T cells from wild-type (WT) or Il6−/− mice (a) and WT or Il21r−/− mice (c) after four days of culture. b, IL-21 mRNA was determined by quantitative RT–PCR (means and s.e.m. for duplicate determinations). d, e, CD4+CD44+ T cells from WT or Il21r−/− mice were stimulated with or without recombinant IL-23 for 48 h. IL-17 and IFN-γ production were determined by intracellular cytokine staining (d) and ELISA (e; open columns, WT; filled columns, Il21r−/−) (asterisk, P < 0.0005; two asterisks, P < 0.003; t-test). f, WT (filled circles) and Il21r−/− (open triangles) mice were immunized with ovalbumin 323–339 peptide (OVA323–339)/CFA. Draining lymph-node cells were assayed for antigen-specific proliferation and cytokine production (means and s.d. for triplicate cultures).

Comment in

  • Immunology: narcissistic helpers.
    Palmer MT, Weaver CT. Palmer MT, et al. Nature. 2007 Jul 26;448(7152):416-8. doi: 10.1038/448416a. Nature. 2007. PMID: 17653176 No abstract available.

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