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

Yuxiang Rui, Tasuku Honjo, Shunsuke Chikuma

研究成果: Article査読

38 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)16073-16078
ページ数6
ジャーナルProceedings of the National Academy of Sciences of the United States of America
110
40
DOI
出版ステータスPublished - 2013 10月 1
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