title: PD-1, but not PD-L1, expressed by islet-reactive CD4+ T cells suppresses infiltration of the pancreas during type 1 diabetes.
abstract: The inhibitory receptor programmed death-1 (PD-1) constrains type 1 diabetes (T1D) in the nonobese diabetic (NOD) mouse. However, how PD-1 influences diabetogenic CD4(+) T cells during natural diabetes is not fully understood. To address this question, we developed a novel model to investigate antigen-specific CD4(+) T cells under physiological conditions in vivo. We transferred a low number of naïve CD4(+) T cells from the BDC2.5 mouse into prediabetic NOD mice to mimic a physiological precursor frequency and allowed the cells to become primed by endogenous autoantigen. Transferred BDC2.5 T cells became activated, differentiated into T-bet(+) IFN-γ-producing cells, and infiltrated the pancreas. In this model, loss of PD-1, but not programmed death ligand-1 (PD-L1), on the antigen-specific CD4(+) T cell resulted in increased cell numbers in the spleen, pancreas-draining lymph node, and pancreas. PD-1 deficiency also increased expression of the chemokine receptor CXCR3. Lastly, histological data showed that a loss of PD-1 caused BDC2.5 cells to penetrate deep into the islet core, resulting in conversion from peri-insulitis to destructive insulitis. These data support a model by which PD-1 regulates islet-reactive CD4(+) T cells in a cell intrinsic manner by suppressing proliferation, inhibiting infiltration of the pancreas, and limiting diabetes.
authors.affiliation: Department of Medicine, Center for Immunology, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Kristen E
authors.initials: KE
authors.lastname: Pauken
authors.forename: Marc K
authors.initials: MK
authors.lastname: Jenkins
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
authors.forename: Brian T
authors.initials: BT
authors.lastname: Fife
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D060890:B7-H1 Antigen / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D007515:Islets of Langerhans / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation / Q000502:physiology; D051379:Mice; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D061026:Programmed Cell Death 1 Receptor
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