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Superantigen Presentation by Airway Smooth Muscle to CD4⁺ T Lymphocytes Elicits Reciprocal Proasthmatic Changes in Airway Function¹

Haviva Veler^*, Aihua Hu^*, Sumbul Fatma^*, Judith S. Grunstein^*, Christine M. DeStephan, Donald Campbell, Jordan S. Orange and Michael M. Grunstein^2,*

^* Division of Pulmonary Medicine and Division of Allergy and Immunology, The Joseph Stokes Jr. Research Institute, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104

Microbial products serving as superantigens (SAgs) have been implicated in triggering various T cell-mediated chronic inflammatory disorders, including severe asthma. Given earlier evidence demonstrating that airway smooth muscle (ASM) cells express MHC class II molecules, we investigated whether ASM can present SAg to resting CD4⁺ T cells, and further examined whether this action reciprocally elicits proasthmatic changes in ASM responsiveness. Coincubation of CD4⁺ T cells with human ASM cells pulsed with the SAg, staphylococcal enterotoxin A (SEA), elicited adherence and clustering of class II and CD3 molecules at the ASM/T cell interface, indicative of immunological synapse formation, in association with T cell activation. This ASM/T cell interaction evoked up-regulated mRNA expression and pronounced release of the Th2-type cytokine, IL-13, into the coculture medium, which was MHC class II dependent. Moreover, when administering the conditioned medium from the SEA-stimulated ASM/T cell cocultures to isolated naive rabbit ASM tissues, the latter exhibited proasthmatic-like changes in their constrictor and relaxation responsiveness that were prevented by pretreating the tissues with an anti-IL-13 neutralizing Ab. Collectively, these observations are the first to demonstrate that ASM can present SAg to CD4⁺ T cells, and that this MHC class II-mediated cooperative ASM/T cell interaction elicits release of IL-13 that, in turn, evokes proasthmatic changes in ASM constrictor and relaxant responsiveness. Thus, a new immuno-regulatory role for ASM is identified that potentially contributes to the pathogenesis of nonallergic (intrinsic) asthma and, accordingly, may underlie the reported association between microbial SAg exposure, T cell activation, and severe asthma.

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 National Heart, Lung, and Blood Institute Grants R01 HL-31467 and R01 HL-61038 (to M.M.G.), and a Career Development Award from Educational Research Trust of the American Academy of Allergy, Asthma and Immunology (to J.S.O.).

² Address correspondence and reprint requests to Dr. Michael M. Grunstein, Division of Pulmonary Medicine, Abramson Research Building, Children’s Hospital of Philadelphia, 34th Street and Civic Center Boulevard, Philadelphia, PA 19104. E-mail address: grunstein{at}email.chop.edu

³ Abbreviations used in this paper: SAg, superantigen; SEA, staphylococcal enterotoxin A; ASM, airway smooth muscle; ACh, acetylcholine; Tmax, maximal isometric contractile force; Rmax, maximal isometric relaxation; MFI, mean fluorescence intensity.