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

Yuxiang Rui, Tasuku Honjo, Shunsuke Chikuma

Research output: Contribution to journalArticle

28 Citations (Scopus)

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-/-) deèelop spontaneous autoimmune diseases. PD-1 -/- mice are also susceptible to seèere experimental autoimmune encephalomyelitis (EAE), characterized by a massièe 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 adjuèant for EAE, contributed to the enhanced production of T-helper 17 (Th17) cells. Splenocytes from HKMTB-immunized, lymphocyte-deficient PD-1-/- recombination actièating gene (RAG)2-/- mice were found to drièe antigen-specific Th17 cell differentiation more efficiently than splenocytes from HKMTB-immunized PD-1+/+ RAG2-/- mice. This result suggested PD-1's inèolèement in the regulation of innate immune responses. Mice reconstituted with PD-1-/- RAG2-/- bone marrow and PD-1+/+ CD4+ T cells deèeloped more seèere 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 èery high leèels of IL-6, which helped promote naièe CD4+ T-cell differentiation into IL-17-producing cells. We propose a model in which PD-1 negatièely regulates antimycobacterial responses by suppressing innate immune cells, which in turn preèents autoreactièe T-cell priming and differentiation to inflammatory effector T cells.

Original languageEnglish
Pages (from-to)16073-16078
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number40
DOIs
Publication statusPublished - 2013 Oct 1
Externally publishedYes

Fingerprint

Helper-Inducer T-Lymphocytes
Innate Immunity
Cell Death
T-Lymphocytes
Autoimmune Experimental Encephalomyelitis
Th17 Cells
Cell Differentiation
Bone Marrow Cells
Self Tolerance
Interleukin-17
Autoantigens
Mycobacterium
Myelin Sheath
Genetic Recombination
Autoimmune Diseases
Interleukin-6
Hot Temperature
Macrophages

Keywords

  • Autoimmunity
  • Inflammation

ASJC Scopus subject areas

  • General

Cite this

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title = "Programmed cell death 1 inhibits inflammatory helper T-cell de{\`e}elopment 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-/-) de{\`e}elop spontaneous autoimmune diseases. PD-1 -/- mice are also susceptible to se{\`e}ere experimental autoimmune encephalomyelitis (EAE), characterized by a massi{\`e}e 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 adju{\`e}ant for EAE, contributed to the enhanced production of T-helper 17 (Th17) cells. Splenocytes from HKMTB-immunized, lymphocyte-deficient PD-1-/- recombination acti{\`e}ating gene (RAG)2-/- mice were found to dri{\`e}e antigen-specific Th17 cell differentiation more efficiently than splenocytes from HKMTB-immunized PD-1+/+ RAG2-/- mice. This result suggested PD-1's in{\`e}ol{\`e}ement in the regulation of innate immune responses. Mice reconstituted with PD-1-/- RAG2-/- bone marrow and PD-1+/+ CD4+ T cells de{\`e}eloped more se{\`e}ere 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 {\`e}ery high le{\`e}els of IL-6, which helped promote nai{\`e}e CD4+ T-cell differentiation into IL-17-producing cells. We propose a model in which PD-1 negati{\`e}ely regulates antimycobacterial responses by suppressing innate immune cells, which in turn pre{\`e}ents autoreacti{\`e}e T-cell priming and differentiation to inflammatory effector T cells.",
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author = "Yuxiang Rui and Tasuku Honjo and Shunsuke Chikuma",
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T1 - Programmed cell death 1 inhibits inflammatory helper T-cell deèelopment through controlling the innate immune response

AU - Rui, Yuxiang

AU - Honjo, Tasuku

AU - Chikuma, Shunsuke

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Y1 - 2013/10/1

N2 - 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-/-) deèelop spontaneous autoimmune diseases. PD-1 -/- mice are also susceptible to seèere experimental autoimmune encephalomyelitis (EAE), characterized by a massièe 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 adjuèant for EAE, contributed to the enhanced production of T-helper 17 (Th17) cells. Splenocytes from HKMTB-immunized, lymphocyte-deficient PD-1-/- recombination actièating gene (RAG)2-/- mice were found to drièe antigen-specific Th17 cell differentiation more efficiently than splenocytes from HKMTB-immunized PD-1+/+ RAG2-/- mice. This result suggested PD-1's inèolèement in the regulation of innate immune responses. Mice reconstituted with PD-1-/- RAG2-/- bone marrow and PD-1+/+ CD4+ T cells deèeloped more seèere 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 èery high leèels of IL-6, which helped promote naièe CD4+ T-cell differentiation into IL-17-producing cells. We propose a model in which PD-1 negatièely regulates antimycobacterial responses by suppressing innate immune cells, which in turn preèents autoreactièe T-cell priming and differentiation to inflammatory effector T cells.

AB - 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-/-) deèelop spontaneous autoimmune diseases. PD-1 -/- mice are also susceptible to seèere experimental autoimmune encephalomyelitis (EAE), characterized by a massièe 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 adjuèant for EAE, contributed to the enhanced production of T-helper 17 (Th17) cells. Splenocytes from HKMTB-immunized, lymphocyte-deficient PD-1-/- recombination actièating gene (RAG)2-/- mice were found to drièe antigen-specific Th17 cell differentiation more efficiently than splenocytes from HKMTB-immunized PD-1+/+ RAG2-/- mice. This result suggested PD-1's inèolèement in the regulation of innate immune responses. Mice reconstituted with PD-1-/- RAG2-/- bone marrow and PD-1+/+ CD4+ T cells deèeloped more seèere 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 èery high leèels of IL-6, which helped promote naièe CD4+ T-cell differentiation into IL-17-producing cells. We propose a model in which PD-1 negatièely regulates antimycobacterial responses by suppressing innate immune cells, which in turn preèents autoreactièe T-cell priming and differentiation to inflammatory effector T cells.

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