GM-CSF-dependent, CD103+ dermal dendritic cells play a critical role in Th effector cell differentiation after subcutaneous immunization - PubMed (original) (raw)
GM-CSF-dependent, CD103+ dermal dendritic cells play a critical role in Th effector cell differentiation after subcutaneous immunization
Irah L King et al. J Exp Med. 2010.
Abstract
Dendritic cells (DCs) play an important role in CD4(+) T helper (Th) cell differentiation and in the initiation of both protective and pathogenic immunity. Granulocyte/macrophage colony-stimulating factor (GM-CSF) is a DC growth factor critical for the induction of experimental autoimmune encephalomyelitis (EAE) and other autoimmune diseases, yet its mechanism of action in vivo is not fully defined. We show that GM-CSF is directly required for the accumulation of radiosensitive dermal-derived langerin(+)CD103(+) DCs in the skin and peripheral lymph nodes under steady-state and inflammatory conditions. Langerin(+)CD103(+) DCs stimulated naive myelin-reactive T cells to proliferate and produce IFN-gamma and IL-17. They were superior to other DC subsets in inducing expression of T-bet and promoting Th1 cell differentiation. Ablation of this subset in vivo conferred resistance to EAE. The current report reveals a previously unidentified role for GM-CSF in DC ontogeny and identifies langerin(+)CD103(+) DCs as an important subset in CD4(+) T cell-mediated autoimmune disease.
Figures
Figure 1.
Langerin+CD103+MHCIIhi dermal DCs are GM-CSF dependent. (A) FACS analysis of dermal mononuclear cells from naive WT and GM-CSF−/− mice. Dot plots are gated on total MHCII+ (left) or langerin+MHCII+ cells (right). (B) Epidermal mononuclear cells from naive WT and GM-CSF−/− mice. Histograms are gated on MHCII+ cells. Shaded histograms indicate isotype control staining. Dot plots (right) are gated on langerin+ epidermal cells. (C) Immunofluorescent staining for langerin (green) and CD103 (red) in ear skin sections from WT and GM-CSF−/− mice. The epidermis lies above the dermis in each image. (D) CD45.2 expression on CD11b+CD103−MHCII+ (left) and CD11b−CD103+MHCII+ (right) dermal cells from mixed bone marrow chimeric mice reconstituted with a 1:1 mixture of CD45.2βc−/− and CD45.1 WT bone marrow cells. (E) Percentage of TRITC+ cells among the langerin+CD11c+CD103+ (left) and CD103− (right) subsets of auricular lymph node cells in WT and GM-CSF−/− mice on days 2, 4, and 7 after ear painting (*, P < 0.05; error bars represent SEM). All data shown are representative of two to four experiments with at least three mice per group. Percentages are shown in A, B, and D. Bars, 10 µm.
Figure 2.
Langerin+CD103+MHCIIhi DCs require GM-CSF signaling to accumulate in the peripheral lymph nodes of MOG-immunized mice. (A) Percentages of CD11c+ subsets in draining lymph nodes of WT, GM-CSF−/−, or βc−/− mice on day 7 after immunization with MOG/CFA. Histograms are based on the gates illustrated in the dot plots (left). (far right) Dot plots are gated on all CD11c+MHCII+ cells. (B and C) Absolute number of total CD11c+MHCII+ cells (B) and DC subsets (C) in draining lymph nodes on day 7 after immunization with MOG/CFA (*, P < 0.05; n.s., not statistically significant; error bars represent SD). (D) Cell-surface profiles of CD103+ and CD103−MHCIIhi lymph node DCs from MOG-immunized WT mice. Shaded histograms indicate background staining. (E) CD45.2 expression on langerin+ DC subsets in cutaneous lymph nodes of CD45.2+→CD45.1+ bone marrow chimeras. Percentages are shown in D and E. Data are representative of three independent experiments with three or more mice per group.
Figure 3.
Functional GM-CSF receptor expression is necessary for accumulation of langerin+CD103+MHCIIhi DCs in the cutaneous lymph nodes during homeostasis. (A) CD103 and MHCII expression on DCs in lymph nodes from unimmunized WT, βc−/−, and GM-CSF−/− mice, gating on CD11c+MHCII+ cells. (B) Total number of DC subsets in cutaneous lymph nodes of naive mice (*, P < 0.05; **, P < 0.01; error bars represent SEM). (C) CD45.1/2 expression on langerin+CD103+MHCIIhi lymph node DCs in unimmunized mixed bone marrow chimeric mice. Irradiated CD45.1+ WT hosts were reconstituted with a 1:1 mixture of either CD45.2+ WT and CD45.1+ WT cells (left) or CD45.2+βc−/− and CD45.1+ WT cells (right). Percentages are shown in A and C. (D) Percentage of cells derived from WT versus βc−/− donors within CD11c+ lymph node DC subsets from mixed bone marrow chimeras (error bars represent SEM). All data in A–D are representative of three separate experiments with at least three mice per group.
Figure 4.
Radiosensitive langerin+CD103+ DCs promote encephalitogenic Th1/Th17 responses and induction of EAE. (A, top) Langerin-DTR→WT chimeric mice were treated with vehicle (left) or DT (right) for 2 d before analysis of cutaneous lymph node cells by flow cytometry. Dot plots are gated on CD11c+MHCII+ cells. (bottom) Gating on langerin+MHCIIhi lymph node cells from MOG-immunized chimeric mice. Percentages are shown. (B) Clinical course of EAE in chimeric mice injected with DT or vehicle alone. Data shown are combined from two separate experiments with five or more mice per group (*, P < 0.05; **, P < 0.002; N.S., not statistically significant; error bars represent SEM). (C) ELISPOT analysis of draining lymph nodes 6 d after immunization of DT-treated chimeric or WT mice and vehicle-treated chimeric mice (*, P < 0.05; **, P < 0.01; error bars represent SEM). Data are representative of two independent experiments with five mice per group.
Figure 5.
CD103+MHCIIhi DCs prime naive myelin-specific T cells and induce Th effector cell differentiation. (A) DC subsets sorted from cutaneous lymph nodes of WT mice 20 h after immunization with MOG/CFA were cultured with purified, CFSE-stained CD45.1+CD4+ 2D2 T cells in the absence or presence of MOG peptide. Anti–I-Ab antibodies were added to some wells. Plots are gated on CD45.1+ T cells. Percentages are shown. Data are representative of four independent experiments. (B) Sorted naive 2D2 T cells were cultured with sorted lymph node DC subsets or unfractionated lymph node DCs in the presence of MOG peptide for 4 d. Cells were restimulated with anti-CD3/-CD28 for 48 h for detection of IFN-γ or IL-17 in supernatants by ELISA (error bars represent SEM). (C) Cells were prepared as described in B but harvested after 96 h of primary culture for real-time RT-PCR analysis. Data shown in B and C are representative of three separate experiments.
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