title: Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response.
abstract: Programmed cell death 1 (PD-1) is an inhibitory coreceptor on immune cells and is essential for self-tolerance because mice genetically lacking PD-1 (PD-1(-/-)) develop spontaneous autoimmune diseases. PD-1(-/-) mice are also susceptible to severe experimental autoimmune encephalomyelitis (EAE), characterized by a massive production of effector/memory T cells against myelin autoantigen, the mechanism of which is not fully understood. We found that an increased primary response of PD-1(-/-) mice to heat-killed mycobacteria (HKMTB), an adjuvant for EAE, contributed to the enhanced production of T-helper 17 (Th17) cells. Splenocytes from HKMTB-immunized, lymphocyte-deficient PD-1(-/-) recombination activating gene (RAG)2(-/-) mice were found to drive antigen-specific Th17 cell differentiation more efficiently than splenocytes from HKMTB-immunized PD-1(+/+) RAG2(-/-) mice. This result suggested PD-1's involvement in the regulation of innate immune responses. Mice reconstituted with PD-1(-/-) RAG2(-/-) bone marrow and PD-1(+/+) CD4(+) T cells developed more severe EAE compared with the ones reconstituted with PD-1(+/+) RAG2(-/-) bone marrow and PD-1(+/+) CD4(+) T cells. We found that upon recognition of HKMTB, CD11b(+) macrophages from PD-1(-/-) mice produced very high levels of IL-6, which helped promote naive CD4(+) T-cell differentiation into IL-17-producing cells. We propose a model in which PD-1 negatively regulates antimycobacterial responses by suppressing innate immune cells, which in turn prevents autoreactive T-cell priming and differentiation to inflammatory effector T cells.
authors.affiliation: Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Yuxiang
authors.initials: Y
authors.lastname: Rui
authors.forename: Tasuku
authors.initials: T
authors.lastname: Honjo
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Chikuma
mesh_terms: D000818:Animals; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D007113:Immunity, Innate / Q000276:immunology*; D015850:Interleukin-6 / Q000276:immunology; D008264:Macrophages / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor / Q000235:genetics / Q000276:immunology*; D017634:Self Tolerance / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
chemical_list: D004268:DNA-Binding Proteins; D015850:Interleukin-6; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; C499308:Rag2 protein, mouse
keywords: autoimmunity; inflammation
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