PD-1 deficiency results in the development of fatal myocarditis in MRL mice

Jian Wang, Il Mi Okazaki, Taku Yoshida, Shunsuke Chikuma, Yu Kato, Fumio Nakaki, Hiroshi Hiai, Tasuku Honjo, Taku Okazaki

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100 Citations (Scopus)

Abstract

The deficiency of programmed cell death 1 (PD-1, Pdcd1), a negative immuno-receptor belonging to the CD28/cytotoxic T lymphocyte antigen 4 (CTLA-4) family, can support various tissue-specific autoimmune conditions. Here, we analyzed the effect of PD-1 deficiency in MRL mice that is genetically predisposed to systemic autoimmunity. MRL-Pdcd1-/- mice developed a fatal myocarditis, which is reminiscent of CTLA-4-deficient (Ctla4-/-) mice. Massive infiltration of CD4+ and CD8+ T cells and myeloid cells was found in hearts of MRL-Pdcd1-/- mice concomitant with the production of high-titer auto-antibodies against cardiac myosin. In contrast to Ctla4-/- mice in which most of the CD4+ T cells are non-specifically activated and invade various organs, T cells in the heart but not in the spleen and lymph nodes are activated in MRL-Pdcd1-/- mice, suggesting that myocarditis is mediated by antigen-specific autoimmune response. Heart infiltrating myeloid cells strongly suppressed the allogenic response of T cells in vitro, suggesting that these Mac1+Gr1+ myeloid cells are phenotypically similar to myeloid suppressor cells, which can be found in tumorbearing hosts. These findings unravel the hidden heart-specific autoimmune predisposition of MRL mice and provide MRL-Pdcd1-/- mice as a useful animal model of lymphocytic myocarditis.

Original languageEnglish
Pages (from-to)443-452
Number of pages10
JournalInternational immunology
Volume22
Issue number6
DOIs
Publication statusPublished - 2010 Apr 21
Externally publishedYes

Keywords

  • Animal model
  • Auto-antibody
  • Autoimmune disease
  • Co-stimulation
  • Genetic predisposition

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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  • Cite this

    Wang, J., Okazaki, I. M., Yoshida, T., Chikuma, S., Kato, Y., Nakaki, F., Hiai, H., Honjo, T., & Okazaki, T. (2010). PD-1 deficiency results in the development of fatal myocarditis in MRL mice. International immunology, 22(6), 443-452. https://doi.org/10.1093/intimm/dxq026