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

Research output: Contribution to journalArticle

78 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<sup>-/-</sup> mice developed a fatal myocarditis, which is reminiscent of CTLA-4-deficient (Ctla4<sup>-/-</sup>) mice. Massive infiltration of CD4<sup>+</sup> and CD8<sup>+</sup> T cells and myeloid cells was found in hearts of MRL-Pdcd1<sup>-/-</sup> mice concomitant with the production of high-titer auto-antibodies against cardiac myosin. In contrast to Ctla4<sup>-/-</sup> mice in which most of the CD4<sup>+</sup> 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<sup>-/-</sup> 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<sup>+</sup>Gr1<sup>+</sup> 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<sup>-/-</sup> 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

Fingerprint

Myocarditis
Myeloid Cells
CTLA-4 Antigen
T-Lymphocytes
Autoimmunity
Cardiac Myosins
Cell Death
Spleen
Animal Models
Lymph Nodes
Antigens
Antibodies

Keywords

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

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Wang, J., Okazaki, I. M., Yoshida, T., Chikuma, S., Kato, Y., Nakaki, F., ... 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

PD-1 deficiency results in the development of fatal myocarditis in MRL mice. / Wang, Jian; Okazaki, Il Mi; Yoshida, Taku; Chikuma, Shunsuke; Kato, Yu; Nakaki, Fumio; Hiai, Hiroshi; Honjo, Tasuku; Okazaki, Taku.

In: International Immunology, Vol. 22, No. 6, 21.04.2010, p. 443-452.

Research output: Contribution to journalArticle

Wang, J, Okazaki, IM, 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, vol. 22, no. 6, pp. 443-452. https://doi.org/10.1093/intimm/dxq026
Wang, Jian ; Okazaki, Il Mi ; Yoshida, Taku ; Chikuma, Shunsuke ; Kato, Yu ; Nakaki, Fumio ; Hiai, Hiroshi ; Honjo, Tasuku ; Okazaki, Taku. / PD-1 deficiency results in the development of fatal myocarditis in MRL mice. In: International Immunology. 2010 ; Vol. 22, No. 6. pp. 443-452.
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