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Phosphatidylinositol Mannoside from Mycobacterium tuberculosis Binds ₅₁ Integrin (VLA-5) on CD4⁺ T Cells and Induces Adhesion to Fibronectin¹

Roxana E. Rojas^2,*,, Jeremy J. Thomas^*, Adam J. Gehring^*, Preston J. Hill, John T. Belisle, Clifford V. Harding^3, and W. Henry Boom^3,*,

^* Department of Medicine, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, OH 44106; Tuberculosis Research Unit and Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106; and Department of Microbiology, Immunology, and Pathology, Colorado State University, Fort Collins, CO 80523

The pathological hallmark of the host response to Mycobacterium tuberculosis is the granuloma where T cells and macrophages interact with the extracellular matrix (ECM) to control the infection. Recruitment and retention of T cells within inflamed tissues depend on adhesion to the ECM. T cells use integrins to adhere to the ECM, and fibronectin (FN) is one of its major components. We have found that the major M. tuberculosis cell wall glycolipid, phosphatidylinositol mannoside (PIM), induces homotypic adhesion of human CD4⁺ T cells and T cell adhesion to immobilized FN. Treatment with EDTA and cytochalasin D prevented PIM-induced T cell adhesion. PIM-induced T cell adhesion to FN was blocked with mAbs against ₅ integrin chain and with RGD-containing peptides. ₅₁ (VLA-5) is one of two major FN receptors on T cells. PIM was found to bind directly to purified human VLA-5. Thus, PIM interacts directly with VLA-5 on CD4⁺ T lymphocytes, inducing activation of the integrin, and promoting adhesion to the ECM glycoprotein, FN. This is the first report of direct binding of a M. tuberculosis molecule to a receptor on human T cells resulting in a change in CD4⁺ T cell function.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institutes of Health Grants AI-27243 and HL-55967 (to W.H.B.) and AI34343 and AI35726 (to C.V.H.), Tuberculosis Prevention and Control Research Unit Contract AI-45244/95383, Grant HHSN26620040091C, and National Institutes of Health, National Institute of Allergy and Infectious Diseases Grant N01-AI-40091.

² Address correspondence and reprint requests to Dr. Roxana E. Rojas, Department of Medicine and Tuberculosis, Research Unit, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, OH 44106-4984. E-mail address: rxr38{at}cwru.edu

³ C.V.H. and W.H.B. share senior authorship.

⁴ Abbreviations used in this paper: ECM, extracellular matrix; BCG, bacillus Calmette Guérin; DPBS, Dulbecco PBS; FN, fibronectin; FSC, forward scatter; HTCA, homotypic T cell adhesion; LAM, lipoarabinomannan; smegLAM, LAM from M. smegmatis; ManLAM, mannose-capped LAM from M. tuberculosis; PIM, phosphatidylinositol mannoside; SPI, soybean PI; SSC, side scatter.

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The JI 2006 177: 2737-2738. [Full Text]