Impaired antigen-specific lymphocyte priming in mice after Toll-like receptor 4 activation via induction of monocytic myeloid-derived suppressor cells

Hiroki Tsukamoto, Sao Kozakai, Yohei Kobayashi, Risako Takanashi, Takuya Aoyagi, Muneo Numasaki, Shoichiro Ohta, Yoshihisa Tomioka

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

In sepsis, the pathology involves a shift from a proinflammatory state toward an immunosuppressive phase. We previously showed that an agonistic anti-TLR4 antibody induced long-term endotoxin tolerance and suppressed antigen-specific secondary IgG production when primed prior to immunization with antigen. These findings led us to speculate that TLR4-induced innate tolerance due to primary infection causes an immunosuppressive pathology in sepsis. Therefore, the mechanism underlying impaired antigen-specific humoral immunity by the TLR4 antibody was investigated. We showed, in a mouse model, that primary antigen-specific IgG responses were impaired in TLR4 antibody-induced tolerized mice, which was the result of reduced numbers of antigen-specific GC B cells and plasma cells. Ovalbumin-specific CD4 and CD8 T-cell responses were impaired in TLR4 antibody-injected OT-I and -II transgenic mice ex vivo. Adoptive transfer studies demonstrated suppression of OVA-specific CD4 and CD8 T-cell responses by the TLR4 antibody in vivo. The TLR4 antibody induced Gr1 + CD11b + myeloid-derived suppressor cell (MDSC) expansion with suppression of T-cell activation. Monocytic MDSCs were more suppressive and exhibited higher expression of PD-L1 and inducible nitric oxidase compared with granulocytic MDSCs. In conclusion, immune tolerance conferred by TLR4 activation induces the expansion of monocytic MDSCs, which impairs antigen-specific T-cell priming and IgG production.

Original languageEnglish
Pages (from-to)546-563
Number of pages18
JournalEuropean Journal of Immunology
Volume49
Issue number4
DOIs
Publication statusPublished - 2019 Apr

Keywords

  • Endotoxin tolerance
  • Innate immunity
  • Myeloid-derived suppressor cells
  • Sepsis
  • TLR 4

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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