title: Thrombospondin-1-dependent immune regulation by transforming growth factor-β2-exposed antigen-presenting cells.
abstract: An important role of transforming growth factor-β (TGF-β) in the development of regulatory T cells is well established. Although integrin-mediated activation of latent TGF-β1 is considered essential for the induction of regulatory T (Treg) cells by antigen-presenting cells (APCs), such an activation mechanism is not applicable to the TGF-β2 isoform, which lacks an integrin-binding RGD sequence in its latency-associated peptide. Mucosal and ocular tissues harbour TGF-β2-expressing APCs involved in Treg induction. The mechanisms that regulate TGF-β activation in such APCs remain unclear. In this study, we demonstrate that murine APCs exposed to TGF-β2 in the environment predominantly increase expression of TGF-β2. Such predominantly TGF-β2-expressing APCs use thrombospondin-1 (TSP-1) as an integrin-independent mechanism to activate their newly synthesized latent TGF-β2 to induce Foxp3(+) Treg cells both in vitro and in vivo. Expression of Treg induction by TGF-β2-expressing APCs is supported by a TSP-1 receptor, CD36, which facilitates activation of latent TGF-β during antigen presentation. Our results suggest that APC-derived TSP-1 is essential for the development of an adaptive regulatory immune response induced by TGF-β2-expressing APCs similar to those located at mucosal and ocular sites. These findings introduce the integrin-independent mechanism of TGF-β activation as an integral part of peripheral immune tolerance associated with TGF-β2-expressing tissues.
authors.forename: Fayaz Ahmad
authors.initials: FA
authors.lastname: Mir
authors.forename: Laura
authors.initials: L
authors.lastname: Contreras-Ruiz
authors.forename: Sharmila
authors.initials: S
authors.lastname: Masli
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D018955:CD36 Antigens / Q000172:deficiency / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D056747:Immunomodulation / Q000187:drug effects / Q000235:genetics; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D019700:Thrombospondin 1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D018955:CD36 Antigens; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D019700:Thrombospondin 1; D053781:Transforming Growth Factor beta2
keywords: antigen presentation; regulatory T cells; thrombospondin-1; transforming growth factor-β2