Abstract
Psoriasis is a common T cell–mediated autoimmune inflammatory disease. We show that blocking the interaction of α1β1 integrin (VLA-1) with collagen prevented accumulation of epidermal T cells and immunopathology of psoriasis. α1β1 integrin, a major collagen-binding surface receptor, was exclusively expressed by epidermal but not dermal T cells. α1β1-positive T cells showed characteristic surface markers of effector memory cells and contained high levels of interferon-γ but not interleukin-4. Blockade of α1β1 inhibited migration of T cells into the epidermis in a clinically relevant xenotransplantation model. This was paralleled by a complete inhibition of psoriasis development, comparable to that caused by tumor necrosis factor-α blockers. These results define a crucial role for α1β1 in controlling the accumulation of epidermal type 1 polarized effector memory T cells in a common human immunopathology and provide the basis for new strategies in psoriasis treatment focusing on T cell–extracellular matrix interactions.
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Acknowledgements
We thank B.J. Nickoloff, M. Gilliet, K.S. Lang and P. Johansen for discussions. We appreciate the excellent technical assistance by C. Dudli and A. Perez. We would further like to thank T. Baechi for help with confocal microscopy. This work was supported by the Swiss National Science Foundation, Biogen-Idec, the Bonizzi-Theler-Foundation and the Wellcome Trust. The authors acknowledge financial support from the UK Department of Health through the National Institute for Health Research Biomedical Research Centre award to Guy's & St Thomas' National Health Service Foundation Trust in partnership with King's College London.
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C.C., O.B. and G.T. performed mouse, cell culture and molecular biology experiments and data analysis. A.T.-K. performed PCR experiments and data analysis. U.L. performed flow cytometry, culture of cell lines and clones and data analysis. A.d.F., V.K. and H.G. provided expertise, reagents and input into manuscript preparation. Experimental design, data analysis and manuscript preparation were carried out by C.C. and F.O.N. All authors read and commented on the paper.
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A.d.F., V.K. and H.G. are former employees of Biogen Idec.
F.O.N. has been consulting for and received lecturing fees from Biogen Idec.
The study has received scientific grant support from Biogen Idec.
Supplementary information
Supplementary Fig. 1
CD3+/CD8+ and CD3+/CD4+ epidermal T cells express α1 integrin. (PDF 133 kb)
Supplementary Fig. 2
Extended phenotype of freshly isolated α1β1+ psoriatic T cells. (PDF 120 kb)
Supplementary Fig. 3
Extended phenotype of α1β1 expressing psoriatic T cell lines. (PDF 269 kb)
Supplementary Fig. 4
Extended phenotype of α1β1 expressing psoriatic T cell clones. (PDF 145 kb)
Supplementary Fig. 5
Efficacy of α1β1 blockade in treatment of established psoriatic skin. (PDF 62 kb)
Supplementary Fig. 6
No induction of apoptosis via monoclonal antibody to α1. (PDF 115 kb)
Supplementary Fig. 7
Migration of T cells through collagen type IV increases α1β1-expression on T cells in vitro. (PDF 34 kb)
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Conrad, C., Boyman, O., Tonel, G. et al. α1β1 integrin is crucial for accumulation of epidermal T cells and the development of psoriasis. Nat Med 13, 836–842 (2007). https://doi.org/10.1038/nm1605
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DOI: https://doi.org/10.1038/nm1605
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