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MHC Class II⁺ Exosomes in Plasma Suppress Inflammation in an Antigen-Specific and Fas Ligand/Fas-Dependent Manner¹

Seon Hee Kim^*,, Nicole R. Bianco^*,, William J. Shufesky^,, Adrian E. Morelli^, and Paul D. Robbins^2,*,

^* Department of Molecular Genetics and Biochemistry and Department of Surgery and Molecular Medicine and T. E. Starzl Transplantation Institutes, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261

Exosomes are 50- to 100-nm vesicles that are formed within the late endocytic compartment and released from a variety of cell types. Previously, we demonstrated that exosomes derived from dendritic cells transduced with adenoviral vectors expressing IL-10, IL-4, or Fas ligand (FasL) produce anti-inflammatory exosomes able to reduce inflammation in a murine paw delayed-type hypersensitivity model, suppress the onset on murine collagen-induced arthritis, and reduce the severity of established collagen-induce arthritis. In this study, we examined the ability of endogenous, blood-borne exosomes to regulate the immune response. Exosomes isolated from plasma of mice immunized to keyhole limpet hemocyanin, but not from naive or OVA-immunized mice, were able to suppress the keyhole limpet hemocyanin-specific delayed-type hypersensitivity inflammatory response. The anti-inflammatory effect was mediated by MHC class II⁺ plasma exosomes that were also FasL⁺ and CD11b⁺, but CD11c^–. Moreover, the anti-inflammatory effect of the MHC class II⁺ plasma-derived exosomes was, in part, dependent upon the presence of FasL in the exosomes and Fas in the recipient mouse. These results suggest that exosomes in the plasma, produced by MHC class II⁺ and CD11b⁺ cells, have the ability to suppress the immune response in an Ag-specific manner in part through a Fas/FasL-dependent manner.

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 Institutes of Health Grants AI56374 (to P.D.R.) and HL075512 and HL077545 (to A.E.M.).

² Address correspondence and reprint requests to Dr. Paul D. Robbins, Department of Molecular Genetics and Biochemistry, W1246 BST, University of Pittsburgh, School of Medicine, Pittsburgh, PA 15261. E-mail address: probb{at}pitt.edu

³ Abbreviations used in this paper: DC, dendritic cell; DTH, delayed-type hypersensitivity; CIA, collagen-induced arthritis; FasL, Fas ligand; KLH, keyhole limpet hemocyanin; TEM, transmission electron microscopy; BM, bone marrow; i.d., intradermal; MHC II, MHC class II.

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