αv Integrin expression by DCs is required for Th17 cell differentiation and development of experimental autoimmune encephalomyelitis in mice
Mridu Acharya, … , Richard O. Hynes, Adam Lacy-Hulbert
Mridu Acharya, … , Richard O. Hynes, Adam Lacy-Hulbert
Published November 22, 2010
Citation Information: J Clin Invest. 2010;120(12):4445-4452. https://doi.org/10.1172/JCI43796.
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Research Article

αv Integrin expression by DCs is required for Th17 cell differentiation and development of experimental autoimmune encephalomyelitis in mice

Abstract

Th17 cells are a distinct lineage of T helper cells that protect the body from bacterial and fungal infection. However, Th17 cells also contribute to inflammatory and autoimmune disorders such as multiple sclerosis. Th17 cell generation requires exposure of naive T cells to the cytokine TGF-β in combination with proinflammatory cytokines. Here we show that differentiation of Th17 cells is also critically dependent on αv integrins. In mice, lack of integrin αv in the immune system resulted in loss of Th17 cells in the intestine and lymphoid tissues. It also led to protection from experimental autoimmune encephalomyelitis (EAE). Further analysis indicated that αv integrins on DCs activated latent TGF-β during T cell stimulation and thereby promoted differentiation of Th17 cells. Furthermore, pharmacologic inhibition of αv integrins using cyclic RGD peptides blocked TGF-β activation and Th17 cell generation in vitro and protected mice from EAE. These data demonstrate that activation of TGF-β by αv-expressing myeloid cells may be a critical step in the generation of Th17 cells and suggest that αv integrins could be therapeutic targets in autoimmune disease.

Authors

Mridu Acharya, Subhankar Mukhopadhyay, Helena Païdassi, Tahseen Jamil, Camille Chow, Stephan Kissler, Lynda M. Stuart, Richard O. Hynes, Adam Lacy-Hulbert

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Figure 4

Expression of αv integrins on DCs is required for T cell responses to latent TGF-β.

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Expression of αv integrins on DCs is required for T cell responses to la...
(A) DCs bound LAP though αv integrins. The number of control and αv-knockout DCs binding to untreated plates or plates coated with LAP, fibronectin (Fn), or vitronectin (Vn) is shown. Data are mean ± SD of 3 wells. (B) Proportion of IL-17–producing T cells generated after in vitro culture of control T cells with DCs from control and αv-tie2 mouse spleens in the presence of anti-CD3, IL-6, and active TGF-β (aTGF-β) or latent TGF-β (lTGF-β) (5 or 20 ng/ml). Data are from 3 separate DC preparations; histograms show the mean ± SEM. Similar results were seen in at least 5 independent experiments. (C and D) Production of IL-17A protein in culture supernatant (C) and mRNA expression of Rorc (D) in T cells stimulated as in C. (E) Contact with DCs was required for T cells to respond to TGF-β activated by αv. Proportion of IL-17–producing T cells generated after culture of T cells from OT2 TCR transgenic mice incubated with the indicated combinations of DCs from C57BL/6 and BALB/c background mice in the presence of OVA peptide, IL-6, and active or latent TGF-β. (F) cRGD peptides inhibited TGF-β activation by DCs. Experimental conditions were the same as in B, with T cells cultured with DCs in the presence of anti-CD3, IL-6, aTGF-β, lTGF-β, and cRGD peptides. Dots represent DC cultures from independent control or αv-tie2 mice. Data are from 2 separate DC preparations from either control or αv-tie2 mice. Similar results were seen in 3 independent experiments.