title: PD-L1 blockade overrides Salmonella typhimurium-mediated diabetes prevention in NOD mice: no role for Tregs.
abstract: Increasingly, evidence suggests that there is a strong environmental component to the development of the autoimmune disease type 1 diabetes. Our previous data showed that NOD mice are protected from developing diabetes after infection with Salmonella typhimurium and there is some evidence that changes within the DC compartment play a crucial role in this protective effect. This paper further characterises this Salmonella-modulated protective phenotype. We find that, contrary to other infection-mediated models of type 1 diabetes protection, there was no expansion of Foxp3(+)  Tregs. Furthermore, transcriptome analysis of DCs identified a distinct Salmonella-induced signature in which the inhibitory receptor PD-L1 was up-regulated. This was confirmed by flow cytometry. In vivo blockade of the PD1/PD-L1 interaction was found to ablate the protective function of Salmonella infection. These data provide evidence for a novel regulatory DC phenotype proficient at controlling autoreactive T cells for an extended duration in the NOD mouse model of diabetes.
authors.affiliation: Department of Pathology, University of Cambridge, Cambridge, UK. san31@cam.ac.uk
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Newland
authors.forename: Jenny M
authors.initials: JM
authors.lastname: Phillips
authors.forename: Pietro
authors.initials: P
authors.lastname: Mastroeni
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
authors.forename: Paola
authors.initials: P
authors.lastname: Zaccone
authors.forename: Anne
authors.initials: A
authors.lastname: Cooke
mesh_terms: D000818:Animals; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D003520:Cyclophosphamide / Q000494:pharmacology; D003713:Dendritic Cells; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000382:microbiology / Q000517:prevention & control*; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D020869:Gene Expression Profiling; D053645:Interleukin-2 Receptor alpha Subunit; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D012481:Salmonella Infections, Animal / Q000276:immunology*; D012486:Salmonella typhimurium / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053645:Interleukin-2 Receptor alpha Subunit; D003520:Cyclophosphamide