Secondary allergic T cell responses are regulated by dendritic cell‐derived thrombospondin‐1 in the setting of allergic eye disease

• Published in: Journal of leukocyte biology Vol. 100; no. 2; pp. 371 - 380
• Main Authors: Smith, R. E., Reyes, N. J., Khandelwal, P., Schlereth, S. L., Lee, H. S., Masli, S., Saban, D. R.
• Format: Journal Article
• Language: English
• Published: England Society for Leukocyte Biology 01.08.2016
• Subjects: AED; Allergens - immunology; Animals; conjunctivitis; Dendritic Cells - immunology; Eye Diseases - chemically induced; Eye Diseases - immunology; Eye Diseases - metabolism; Hypersensitivity - immunology; Hypersensitivity - metabolism; Inflammation, Extracellular Mediators, & Effector Molecules; Lymphocyte Activation; Mice; Mice, Inbred C57BL; Mice, Knockout; Ovalbumin - toxicity; T-Lymphocytes - immunology; Th2; Thrombospondin 1 - physiology; AED; conjunctivitis; Th2
• ISSN: 0741-5400; 1938-3673
• DOI: 10.1189/jlb.3A0815-357RR

TSP‐1 is expressed by DCs and regulates secondary responses of allergic T cells in a mouse model of AED. Allergic eye disease, as in most forms of atopy, ranges in severity among individuals from immediate hypersensitivity to a severe and debilitating chronic disease. Dendritic cells play a key role in stimulating pathogenic T cells in allergen re‐exposure, or secondary responses. However, molecular cues by dendritic cells underpinning allergic T cell response levels and the impact that this control has on consequent severity of allergic disease are poorly understood. Here, we show that a deficiency in thrombospondin‐1, a matricellular protein known to affect immune function, has subsequent effects on downstream T cell responses during allergy, as revealed in an established mouse model of allergic eye disease. More specifically, we demonstrate that a thrombospondin‐1 deficiency specific to dendritic cells leads to heightened secondary T cell responses and consequent clinical disease. Interestingly, whereas thrombospondin‐1‐deficient dendritic cells augmented activity of allergen‐primed T cells, this increase was not recapitulated with naïve T cells in vitro. The role of dendritic cell‐derived thrombospondin‐1 in regulating secondary allergic T cell responses was confirmed in vivo, as local transfer of thrombospondin‐1‐sufficient dendritic cells to the ocular mucosa of thrombospondin‐1 null hosts prevented the development of augmented secondary T cell responses and heightened allergic eye disease clinical responses. Finally, we demonstrate that topical instillation of thrombospondin‐1‐derived peptide reduces T cell activity and clinical progression of allergic eye disease. Taken together, this study reveals an important modulatory role of dendritic cell‐derived thrombospondin‐1 on secondary allergic T cell responses and suggests the possible dysregulation of dendritic cell‐derived thrombospondin‐1 expression as a factor in allergic eye disease severity.