Interleukin-10-mediated cellular interactions in the regulation of cutaneous immune responses
Final Report Abstract
The defense against microbial infection by innate and adaptive immune responses bears the risk of inflammatory „collateral“ damage to host tissue. Interleukin-10 plays a central role in the control mechanisms, which limit the vigor of inflammatory responses in order to prevent immunopathology. Efficient control of immune responses to different stimuli seems to require the release of IL-10 from different cellular sources, since our initial experiments in cell typespecific IL-10 knock out mouse strains revealed distinct and non-redundant functions of IL- 10-derived from T cells or macrophages. In the context of this project, we analyzed immune responses in mice with a selective knock out of the IL-10 gene in additional cells types. While B cells are a prominent source of IL-10 in various responses, defining non-redundant roles of B cell-derived IL-10 proved difficult. IL-10-producing regulatory B (“B10“) cells were reported critical in the control of T cell responses to contact allergens. Contact hypersensitivity, however, was not altered in our B cell-specific IL-10 knock out mice, despite our demonstration of efficient inactivation of the IL-10 gene in B cells and in particular also in the “B10” cell subset. Likewise, B cell-specific IL-10 mutants did not display alterations of innate responses and showed no signs of the inflammatory bowel disease, which is a prominent feature of IL-10-/- and T cell-specific knock out mice. Thus, our findings question a broad relevance of IL-10-dependent regulatory B cell functions. Our data suggest that B cellderived IL-10 may be important in the control of T cell immunity to some but not other viruses. Selective knock out of the IL-10 gene in mast cells did not result in deregulated contact hypersensitivity disproving a recent report of IL-10-dependent regulation of contact allergy by mast cells. We think that the discrepancies between published studies that were based on adoptive transfer experiments and our work in cell type-specific IL-10 knock out mice emphasize that adoptive transfer systems can yield misleading results. Selective knock out of the IL-10 gene in dendritic cells revealed non-redundant functions of IL-10 from DCs in the control of T cell responses. From our findings of cell type-specific IL-10 effects, we conclude that IL-10 must primarily act in a parakrine fashion with IL-10 effects strictly confined to the vicinity of the IL-10-releasing cell. This local confinement, which may rely on various mechanisms, is important since it could impede therapeutic effects of systemically administrated exogenous IL-10. Glycosaminoglycan (GAG)-binding and rapid dissociation of the IL-10 dimer could contribute to local restrictions of IL-10 effects. We succeeded in the generation of a spectrum of IL-10 proteins with mutations of a putative GAG-binding site. We demonstrated intact bioactivity of these proteins and are presently determining their interaction with GAGs. Furthermore, we created a recombinant IL-10 protein with covalently linked monomers and therefore increased stability, which shows excellent bioactivity. We are currently investigating the in vivo therapeutic potential of this mutant protein in inflammatory conditions.
Publications
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Distinct Functions of Interleukin-10 Derived from Different Cellular Sources. Cur Immunol Rev. 2008; 4: 37-42
Roers A, Müller W
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Regulatory T cell-derived interleukin-10 limits inflammation at environmental interfaces. Immunity. 2008; 28:546-58
Rubtsov YP, Rasmussen JP, Chi EY, Fontenot J, Castelli L, Ye X, Treuting P, Siewe L, Roers A, Henderson WR Jr, Muller W, Rudensky AY
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Nonredundant roles for B cell-derived IL-10 in immune counter-regulation. J Immunol. 2009;183:2312-20
Madan R, Demircik F, Surianarayanan S, Allen JL, Divanovic S, Trompette A, Yogev N, Gu Y, Khodoun M, Hildeman D, Boespflug N, Fogolin MB, Gröbe L, Greweling M, Finkelman FD, Cardin R, Mohrs M, Müller W, Waisman A, Roers A, Karp CL
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TLR-2-activated B cells suppress Helicobacter-induced preneoplastic gastric immunopathology by inducing T regulatory-1 cells. J Immunol. 2011;186:878-90
Sayi A, Kohler E, Toller IM, Flavell RA, Müller W, Roers A, Müller A
