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The development of antigen\u2010specific therapies that suppress disease\u2010related, but not unrelated immune responses in general, is an important goal of biomedical research. We have previously shown that delivery of myelin peptides to liver sinusoidal endothelial cells (LSECs) using LSEC\u2010targeting nanoparticles provides effective protection from CD4 T\u2010cell\u2010driven autoimmune encephalomyelitis. Here, we investigated whether this methodology might also serve antigen\u2010specific treatment of a CD8 T\u2010cell\u2010driven autoimmune disease. As a model for CD8 T\u2010cell\u2010mediated autoimmunity, we used OT\u20101 T\u2010cell\u2010driven cholangitis in K14\u2010OVAp mice expressing the cognate MHC I\u2010restricted SIINFEKL peptide in cholangiocytes. To study whether peptide delivery to LSECs could modulate cholangitis, SIINFEKL peptide\u2010conjugated nanoparticles were administered intravenously one day before transfer of OT\u20101 T cells; five days after cell transfer, liver pathology and hepatic infiltrates were analysed. SIINFEKL peptide\u2010conjugated nanoparticles were rapidly taken up by LSECs in vivo, which effectively cross\u2010presented the delivered peptide on MHC I molecules. Intriguingly, K14\u2010OVAp mice receiving SIINFEKL\u2010loaded nanoparticles manifested significantly reduced liver damage compared with vehicle\u2010treated K14\u2010OVAp mice. Mechanistically, treatment with LSEC\u2010targeting SIINFEKL\u2010loaded nanoparticles significantly reduced the number of liver\u2010infiltrating OT\u20101 T cells, which up\u2010regulated expression of the co\u2010inhibitory receptor PD\u20101 and down\u2010regulated cytotoxic effector function and inflammatory cytokine production. These findings show that tolerogenic LSECs can effectively internalize circulating nanoparticles and cross\u2010present nanoparticle\u2010bound peptides on MHC I molecules. Therefore, nanoparticle\u2010mediated autoantigen peptide delivery to LSECs might serve the antigen\u2010specific treatment of CD8 T\u2010cell\u2010driven autoimmune disease.<\/jats:p>","DOI":"10.1111\/imm.13298","type":"journal-article","created":{"date-parts":[[2020,12,21]],"date-time":"2020-12-21T22:58:18Z","timestamp":1608591498000},"page":"452-463","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Nanoparticle\u2010mediated targeting of autoantigen peptide to cross\u2010presenting liver sinusoidal endothelial cells protects from CD8 T\u2010cell\u2010driven autoimmune cholangitis"],"prefix":"10.1111","volume":"162","author":[{"given":"Antonella","family":"Carambia","sequence":"first","affiliation":[{"name":"Department of Medicine I University Medical Centre Hamburg\u2010Eppendorf Hamburg 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