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. 2011 Apr 22;34(4):554-65.
doi: 10.1016/j.immuni.2011.01.020.

Th17 cells express interleukin-10 receptor and are controlled by Foxp3⁻ and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner

Samuel Huber  1 , Nicola Gagliani, Enric Esplugues, William O'Connor Jr, Francis J Huber, Ashutosh Chaudhry, Masahito Kamanaka, Yasushi Kobayashi, Carmen J Booth, Alexander Y Rudensky, Maria Grazia Roncarolo, Manuela Battaglia, Richard A Flavell
Affiliations

V体育官网入口 - Th17 cells express interleukin-10 receptor and are controlled by Foxp3⁻ and Foxp3+ regulatory CD4+ T cells in an interleukin-10-dependent manner

Samuel Huber et al. Immunity. .

Abstract

T helper 17 (Th17) cells are important for host defense against extracellular microorganisms. However, they are also implicated in autoimmune and chronic inflammatory diseases, and as such need to be tightly regulated VSports手机版. The mechanisms that directly control committed pathogenic Th17 cells in vivo remain unclear. We showed here that IL-17A-producing CD4+ T cells expressed interleukin-10 receptor α (IL-10Rα) in vivo. Importantly, T cell-specific blockade of IL-10 signaling led to a selective increase of IL-17A+IFN-γ⁻ (Th17) and IL-17A+IFN-γ+ (Th17+Th1) CD4+ T cells during intestinal inflammation in the small intestine. CD4+Foxp3⁻ IL-10-producing (Tr1) cells and CD4+Foxp3+ regulatory (Treg) cells were able to control Th17 and Th17+Th1 cells in an IL-10-dependent manner in vivo. Lastly, IL-10 treatment of mice with established colitis decreased Th17 and Th17+Th1 cell frequencies via direct signaling in T cells. Thus, IL-10 signaling directly suppresses Th17 and Th17+Th1 cells. .

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Figure 1
Figure 1. Co-localization of Tr1 and Th17 cells in the small intestine after CD3-specific antibody treatment
Foxp3 RFP IL-10 eGFP double reporter mice were injected i.p. with anti-CD3 at 0 and 48 hours (see arrows in panel A). (A) Serum concentrations of IL-17A and IL-10 (Mean ± SEM). (B) Cells were isolated from different organs as indicated. Foxp3 RFP and IL-10 eGFP expression was measured in freshly isolated cells. IL-17A and IFN-γ expression was measured in re-stimulated cells using intracellular cytokine staining (ICS). Cells are gated on CD4+ TCRβ+. Numbers in quadrants indicate percentage of cells. (C) CD4+TCRβ+Foxp3 RFP− IL-10 eGFP+ (CD45.2+) cells were isolated from the small intestine after anti-CD3 treatment. ICS was performed for IL-17A, IFN-γ, IL-4 and TNF-α (Upper panel). The suppressive capacity was measured by CFSE dilution of CD45.1+ responder cells. TGF-β, IL-10Rα and CTLA-4 antibodies were added as indicated (Lower panel). Numbers in quadrants indicate percentage of cells. Results are representative of at least three independent experiments.
Figure 2
Figure 2. IL-10Rα is highly expressed on IL-17A producing CD4+ T cells
IL-10Rα expression was measured using flow cytometry. (A) Cells are gated on naive T cells (CD45.2+CD4+TCRβ+Foxp3−CD44−CD62Lhi) isolated from the spleen and lymph nodes of untreated Foxp3 RFP IL-17A eGFP reporter mice. (B) Cells are gated on CD4+TCRβ+CD44hi cells from the small intestine after anti-CD3 treatment. (C) CD4+CD45.2+Foxp3−CD45RBhi cells were isolated from the spleen of Foxp3-RFP IL-17A-eGFP double reporter mice and injected i.p. into CD45.1+Rag1−/− mice. Cells are gated on CD4+CD45.2+CD44hi IL-17A eGFP+ cells isolated from the mLN three weeks after the transfer. Grey area represents the isotype control. Results are representative of at least two independent experiments.
Figure 3
Figure 3. T-cell specific blockade of IL-10 signaling leads to increased mortality after anti-CD3 treatment
Cd4-DNIL-10R (Tg) or WT mice were injected with anti-CD3. (A) Mass loss (Mean ± SEM; WT: n=8; Tg: n=10) and mortality (cumulative from three experiments) are shown. (B–D) Mice were analyzed 52 hours after the first injection. (B) IL-17A, IFN-γ and TNF-α serum concentrations (Mean ± SEM; WT: n=7; Tg: n=4). (C) Cells were isolated from the small intestine and IL-17A, IFN-γ and TNF-α expression analyzed using ICS. Numbers in quadrants indicate percentage of cells. (D) Statistical overview of different T cell subsets in the small intestine after anti-CD3 injection as determined by ICS. Each dot represents one mouse. Lines indicate mean. Cells were gated on CD4+TCRβ+ events. Results are representative of at least 3 independent experiments.
Figure 4
Figure 4. IL-10 signaling in T cells inhibits the proliferation of IL-17A producing cells
(A) BrdU uptake was measured in CD4+TCRβ+IL-17A eGFP+ cells isolated from WT and Cd4-DNIL-10R mice (left panel). BrdU was injected 12 hours before mice were sacrificed. Time course experiment of total numbers of CD4+TCRβ+IL-17A+ cells after CD3-specific antibody treatment (Mean ± SEM; WT: 0h, n=4; 48h, n=2; 52h, n=5; 96h, n=5; Tg: 0h, n=4; 48h, n=2; 52h, n=4; 96h, n=5) (right panel). (B) Foxp3 RFP and IL-10 eGFP expression was measured in freshly isolated cells. Cells are gated on CD4+TCRβ+ events. A (left panel) and B: Mice were analyzed 52 hours after the first anti-CD3 injection. A (right panel) and B: Data are cumulative from three independent experiments. A (left panel): Data are representative of three independent experiments.
Figure 5
Figure 5. Tr1 cells suppress disease mediated by transfer of in vivo differentiated IL-17A+IFN-γ− and IL-17A+IFN-γ+ CD4+ T cells into Rag1−/− mice via IL-10
IL-17A producing T cells were isolated from the colon and mLN as described in Figure S4. Tr1 cells were isolated from the small intestine of anti-CD3 treated mice and injected i.p. alone or together with IL-17A+ eGFP+ (IL-17A+) cells (WT or Cd4-DNIL-10R (Tg)) into Rag1−/− mice (A) Mass loss, (B) endoscopic and (C) histological colitis score were measured. Each dot represents one mouse. Lines indicate mean. (D) Representative endoscopic findings are shown. Note the bleeding (arrowhead), loss of transluceny, stool inconsistency (*), fibrin (**) and increased mucosal granularity (#) in the mice receiving IL-17A+ (WT), IL-17A+ (Tg) + Tr1 and IL-17A+ (Tg) cells. (E) Representative HE sections of colon are shown. The overall morphology in the colon of mice receiving IL-17A+ (WT)+Tr1 and Tr1 cells was not different from controls. Colons from mice receiving IL-17A+ (WT), IL-17A+ (Tg) + Tr1 and IL-17A+ (Tg) cells all had significant inflammation (*), crypt loss (arrowhead), edema (**), and moderate to marked mucosal hyperplasia (double arrows). HE Scale bars = 1000μm. Results are cumulative from 3 independent experiments.
Figure 6
Figure 6. Treg cells suppress disease mediated by transfer of in vivo differentiated IL-17A+IFN-γ− and IL-17A+IFN-γ+ CD4+ T cells into Rag1−/− mice via IL-10
IL-17A producing T cells were isolated from the colon and mLN as described in Figure S4. CD4+TCRbeta+Foxp3 YFP+ (Treg cells) were isolated from the spleen of Foxp3-cre-YFP-Il10flox/flox (Treg Il10−/−) or Foxp3-cre-YFP-Il10flox/wt (Treg WT) control mice after anti-CD3 treatment. Treg cells were injected i.p. into Rag1−/− mice alone or together with IL-17A+ eGPF+ (IL-17A+) T cells (WT or Cd4-DNIL-10R (Tg)). (A) Mass loss, (B) endoscopic and (C) histological colitis score were measured. Each dot represents one mouse. Lines indicate mean. (D) Representative endoscopic findings are shown. Note the bleeding (arrowhead), loss of transluceny, stool inconsistency (*), fibrin (**) and increased mucosal granularity (#). (E) Representative HE sections of colon. The overall morphology of the colon from mice receiving IL-17A+ (WT) + Treg (WT) cells was not different from controls (See Figure 5E). Colons from mice receiving IL-17A+ (WT), IL-17A+ (WT)+Treg (Il10−/−), IL-17A+ (Tg), and IL-17A+ (Tg)+Treg cells all had significant inflammation (*), variable crypt loss (arrowheads), edema (**), and moderate to marked mucosal hyperplasia (M). Luminal flooding with neutrophils was observed in some mice with server colitis (arrow). Scale bars = 500μm. Results are representative of three independent experiments using WT Treg and two using Foxp3-cre-YFP-Il10flox/flox Treg cells.
Figure 7
Figure 7. IL-10 inhibits IL-17A+IFN-γ− and IL-17A+IFN-γ+ CD4+ T cells in the T-cell transfer colitis model
CD4+CD45.2+Foxp3−CD45RBhi cells (WT and Cd4-DNIL-10R transgenic) were injected i.p. into CD45.1+Rag1−/− mice. Three to four weeks later Rag1−/− mice were injected three times on every other day with IL-10 (75ng/mouse) or PBS i.v.. Cells were isolated from the mLN and ICS for IL-17A, IFN-γ, and TNF-α was performed (top). Cells were gated on CD4+CD45.2+ events. Numbers in quadrants indicate percentage of cells. (Bottom) Each dot represents one mouse. Lines indicate mean. Results are cumulative from three independent experiments.
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