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α1β1 integrin is crucial for accumulation of epidermal T cells and the development of psoriasis

Nature Medicine volume 13, pages 836–842 (2007)Cite this article

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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Figure 1: Expression of α1β1 on human epidermal but not dermal T cells in psoriasis.
Figure 2: Expression of α1β1 defines a population of epidermal type 1 polarized effector memory T cells in psoriasis.
Figure 3: Expansion of epidermal but not dermal T cells correlates with epidermal psoriasiform changes.
Figure 4: Blockade of α1β1 inhibits migration of T cells through collagen type IV in vitro and accumulation of epidermal T cells in vivo.
Figure 5: Treatment with mAb to α1 inhibits development of psoriasis in the AGR psoriasis mouse model.
Figure 6: Efficacy of α1β1 blockade in the presence of an activated immune compartment in uninvolved psoriatic skin.

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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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Author notes

  1. Onur Boyman

    Present address: Present address: Division of Immunology and Allergy, Department of Medicine, Centre Hospitalier Universitaire Vaudois, Rue du Bugnon 46, CH-1011 Lausanne, Switzerland.,

  2. Onur Boyman and Giulia Tonel: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Dermatology, University Hospital of Zurich, Gloriastrasse 31, Zurich, 8091, Switzerland

    Curdin Conrad, Onur Boyman, Giulia Tonel & Adrian Tun-Kyi

  2. Division of Genetics and Molecular Medicine, St. John's Institute of Dermatology, King's College London School of Medicine, Floor 8 Guy's Tower, Guy's Hospital, St. Thomas' Street, London, SE19RT, UK

    Giulia Tonel, Ute Laggner & Frank O Nestle

  3. Biogen Idec Inc., 14 Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Antonin de Fougerolles, Victor Kotelianski & Humphrey Gardner

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Contributions

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.

Corresponding authors

Correspondence to Curdin Conrad or Frank O Nestle.

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Competing interests

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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