title: Secondary allergic T cell responses are regulated by dendritic cell-derived thrombospondin-1 in the setting of allergic eye disease.
abstract: 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.
authors: Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina, USA;
authors: R E
authors: RE
authors: Smith
authors: Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina, USA;
authors: N J
authors: NJ
authors: Reyes
authors: Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA.
authors: P
authors: P
authors: Khandelwal
authors: Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA.
authors: S L
authors: SL
authors: Schlereth
authors: Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA.
authors: H S
authors: HS
authors: Lee
authors: Department of Ophthalmology, Boston University Medical Center, Boston, Massachusetts, USA; and.
authors: S
authors: S
authors: Masli
authors: Department of Ophthalmology, Duke University School of Medicine, Durham, North Carolina, USA; Department of Immunology, Duke University School of Medicine, Durham, North Carolina, USA; daniel.saban@duke.edu.
authors: D R
authors: DR
authors: Saban
mesh_terms: D000485:Allergens / Q000276:immunology*; D000818:Animals; D003713:Dendritic Cells / Q000276:immunology*; D005128:Eye Diseases / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D006967:Hypersensitivity / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000633:toxicity; D013601:T-Lymphocytes / Q000276:immunology*; D019700:Thrombospondin 1 / Q000502:physiology*
chemical_list: D000485:Allergens; D019700:Thrombospondin 1; C585483:Thbs1 protein, mouse; D010047:Ovalbumin
keywords: AED; Th2; conjunctivitis