title: Deficiency of annexin A1 in CD4+ T cells exacerbates T cell-dependent inflammation.
abstract: Annexin A1 (AnxA1) is recognized as an endogenous anti-inflammatory molecule. However, its effects on the adaptive immune response and, in particular, on T cells remain unclear. In this study, we investigated the actions of AnxA1 in three distinct models of T cell-mediated inflammation. In contact hypersensitivity, collagen-induced arthritis, and inflammation induced by OT-II TCR transgenic T cells responding to OVA, AnxA1 deficiency significantly increased Ag-induced T cell proliferation and the resultant level of inflammation. In the contact hypersensitivity model, this was associated with increased adhesion of CD4(+) T cells, CD8(+) T cells, and neutrophils in the dermal microvasculature, as well as increased T cell expression of RORγt and IL-17A. In collagen-induced arthritis, deficiency of endogenous AnxA1 increased susceptibility to arthritis and Ag-specific T cell activation. Deficiency of AnxA1 also increased OVA-induced cutaneous delayed-type hypersensitivity and IFN-γ and IL-17 release. Transfer experiments using CD4(+) T cells from AnxA1(-/-) mice demonstrated that the absence of AnxA1 solely in T cells resulted in increased inflammatory responses in wild-type recipients. Similarly, experiments using AnxA1(-/-) OT-II CD4(+) T cells demonstrated that the absence of AnxA1 in T cells was sufficient to induce increased Ag-specific CD4(+) T cell proliferation in vivo, augment T cell production of IFN-γ, IL-17, TNF, and IL-6, and increase Akt, ERK, and p38 activation. Together, these findings indicate that T cell-expressed AnxA1 functions to attenuate T cell-driven inflammatory responses via T cell-intrinsic effects on intracellular signaling, proliferation, and Th1/Th17 cytokine release.
authors.affiliation: Centre for Inflammatory Diseases, Department of Medicine, Southern Clinical School, Monash University Faculty of Medicine, Nursing and Health Sciences, Monash Medical Centre, Clayton, Victoria 3168, Australia. yuan.yang@monash.edu
authors.forename: Yuan H
authors.initials: YH
authors.lastname: Yang
authors.forename: Wuqi
authors.initials: W
authors.lastname: Song
authors.forename: James A
authors.initials: JA
authors.lastname: Deane
authors.forename: Wenping
authors.initials: W
authors.lastname: Kao
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Ooi
authors.forename: Devi
authors.initials: D
authors.lastname: Ngo
authors.forename: A Richard
authors.initials: AR
authors.lastname: Kitching
authors.forename: Eric F
authors.initials: EF
authors.lastname: Morand
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hickey
mesh_terms: D000818:Animals; D017305:Annexin A1 / Q000172:deficiency* / Q000276:immunology; D001169:Arthritis, Experimental / Q000276:immunology / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002448:Cell Adhesion; D017449:Dermatitis, Allergic Contact / Q000276:immunology / Q000473:pathology; D004789:Enzyme Activation / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology; D006968:Hypersensitivity, Delayed / Q000276:immunology / Q000473:pathology; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics; D008213:Lymphocyte Activation; D008222:Lymphokines / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000096:biosynthesis / Q000235:genetics; D010047:Ovalbumin / Q000276:immunology / Q000633:toxicity; D010081:Oxazolone / Q000276:immunology / Q000633:toxicity; D010446:Peptide Fragments / Q000276:immunology / Q000633:toxicity; D015398:Signal Transduction / Q000276:immunology; D013047:Specific Pathogen-Free Organisms
chemical_list: D017305:Annexin A1; D020381:Interleukin-17; D008222:Lymphokines; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C111390:OVA 323-339; D010446:Peptide Fragments; C539901:Rorc protein, mouse; C573274:annexin A1, mouse; D010081:Oxazolone; D010047:Ovalbumin