Inhibition of macropinocytosis blocks antigen presentation of type II collagen in vitro and in vivo in HLA-DR1 transgenic mice |
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| Authors: | Alexei von Delwig Catharien MU Hilkens Daniel M Altmann Rikard Holmdahl John D Isaacs Clifford V Harding Helen Robertson Norman McKie John H Robinson |
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| Institution: | (1) Musculoskeletal Research Group, Clinical Medical Sciences, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne, UK;(2) Human Disease Immunogenetics Group, Department of Infectious Diseases, Imperial College School of Medicine, Hammersmith Hospital, London, UK;(3) Department of Cell and Molecular Biology, Lund University, Lund, Sweden;(4) Department of Pathology, Case Western Reserve University, Cleveland, OH, USA;(5) BioImaging Facility, Clinical Laboratory Sciences, University of Newcastle upon Tyne, Framlington Place, Newcastle upon Tyne, UK |
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| Abstract: | Professional antigen-presenting cells, such as dendritic cells, macrophages and B cells have been implicated in the pathogenesis
of rheumatoid arthritis, constituting a possible target for antigen-specific immunotherapy. We addressed the possibility of
blocking antigen presentation of the type II collagen (CII)-derived immunodominant arthritogenic epitope CII259–273 to specific CD4 T cells by inhibition of antigen uptake in HLA-DR1-transgenic mice in vitro and in vivo. Electron microscopy, confocal microscopy, subcellular fractionation and antigen presentation assays were used to establish
the mechanisms of uptake, intracellular localization and antigen presentation of CII by dendritic cells and macrophages. We
show that CII accumulated in membrane fractions of intermediate density corresponding to late endosomes. Treatment of dendritic
cells and macrophages with cytochalasin D or amiloride prevented the intracellular appearance of CII and blocked antigen presentation
of CII259–273 to HLA-DR1-restricted T cell hybridomas. The data suggest that CII was taken up by dendritic cells and macrophages predominantly
via macropinocytosis. Administration of amiloride in vivo prevented activation of CII-specific polyclonal T cells in the draining popliteal lymph nodes. This study suggests that selective
targeting of CII internalization in professional antigen-presenting cells prevents activation of autoimmune T cells, constituting
a novel therapeutic strategy for the immunotherapy of rheumatoid arthritis. |
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