Altered availability of PD-1/PD ligands is associated with the failure to control autoimmunity in NOD mice.
Costimulation via the PD-1 and B7-H1/B7-DC pathway regulates immunity. We investigated whether the PD-1/PD-L pathway is impaired in autoimmune diabetes. A progressive increase in the expression of PD-1 and B7-H1/B7-DC on T cells and APC, respectively, was observed in the pancreatic lymph nodes of female non-obese diabetic (NOD) mice as they developed diabetes. A significantly decreased expression of PD-1 and B7-H1/B7-DC on T cells and APC, respectively, was observed in the periphery of prediabetic NOD mice versus non-diabetic C57BL/6 strain. NOD islets also displayed a reduced capacity to upregulate B7-H1 following exposure to inflammatory cytokines. In vivo blocking studies in NOD/B7-2KONOD mice revealed that B7-H1 and B7-DC positively costimulate autoreactive CD4 and CD8 T cells and may co-operate with B7-2 to augment priming and expansion of naïve autoreactive T cells. In summary, these data suggest that diabetes susceptibility in NOD mice is associated with altered PD-1/PD-L availability.
Yadav
Deepak
D
Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, United States. dyadav@ucsd.edu
Hill
Natasha
N
Yagita
Hideo
H
Azuma
Miyuki
M
Sarvetnick
Nora
N
D000367:Age Factors; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen / Q000235:genetics / Q000276:immunology*; D060890:B7-H1 Antigen; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology*; D018450:Disease Progression; D004198:Disease Susceptibility / Q000276:immunology; D005260:Female; D008024:Ligands; D008198:Lymph Nodes / Q000276:immunology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D010179:Pancreas / Q000276:immunology; D010455:Peptides / Q000235:genetics / Q000276:immunology*; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology; D013601:T-Lymphocytes / Q000378:metabolism
D000943:Antigens, Differentiation; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008024:Ligands; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor