Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response

• Published in: Proceedings of the National Academy of Sciences - PNAS 2013-10, Vol.110 (40), p.16073-16078
• Main Authors: Rui, Yuxiang, Honjo, Tasuku, Chikuma, Shunsuke
• Format: Article
• Language: English
• Subjects: adjuvants; Animals; Apoptosis; Autoimmune diseases; Biological Sciences; bone marrow; cell differentiation; Cells; Cytokines; DNA-Binding Proteins - genetics; DNA-Binding Proteins - immunology; encephalitis; Encephalomyelitis, Autoimmune, Experimental - immunology; Enzyme-Linked Immunosorbent Assay; Experimental autoimmune encephalomyelitis; genes; Genetics; Immunity, Innate - immunology; Immunization; innate immunity; interleukin-6; Interleukin-6 - immunology; Macrophages; Macrophages - immunology; Mice; Mice, Knockout; Mycobacterium tuberculosis; myelin sheath; Programmed Cell Death 1 Receptor - genetics; Programmed Cell Death 1 Receptor - immunology; Rodents; Self Tolerance - immunology; Splenocytes; T cell antigen receptors; T cell receptors; T lymphocytes; T-Lymphocytes, Helper-Inducer - immunology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1315828110

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.