Minor contribution of cytotoxic T lymphocyte antigen 4 and programmed cell death 1 ligand 1 in immune tolerance against mouse thyrotropin receptor in mice

DOI 機関リポジトリ HANDLE
  • Yasui Junichi
    Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University Department of Endocrinology and Metabolism, Nagasaki University Graduate School of Biomedical Sciences
  • Nakahara Mami
    Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University
  • Shimamura Mika
    Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University
  • Kurashige Tomomi
    Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University
  • Yasui Kazuaki
    Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University
  • Abiru Norio
    Department of Endocrinology and Metabolism, Nagasaki University Graduate School of Biomedical Sciences
  • Kawakami Atsushi
    Department of Endocrinology and Metabolism, Nagasaki University Graduate School of Biomedical Sciences
  • Nagayama Yuji
    Department of Molecular Medicine, Atomic Bomb Disease Institute, Nagasaki University

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We have previously shown that wild type (wt) mice exhibit susceptibility to immunization with human (h) thyrotropin receptor (TSHR), but resistance to mouse (m) TSHR, while TSHR knockout (KO) mice are susceptible to mTSHR, indicating the existence of robust immune tolerance against the mTSHR in wt mice. This tolerance may be mediated by either centrally or peripherally. We here explored the contribution of a peripheral arm of immune tolerance against the mTSHR by using antibodies to deplete regulatory T cells (Tregs), to antagonize co-inhibitory molecules and/or to stimulate co-stimulatory molecules. Antagonistic anti-co-inhibitory molecules, cytotoxic T lymphocyte antigen 4 (CTLA4) and programmed cell death 1 ligand 1 (PDL1), induced only low levels of anti-TSHR antibodies without induction of hyperthyroidism in a mouse Graves’ model. In this experimental setting, antibody levels were significantly higher in THSR+/- mice than wt mice. However, agonistic anti-co-stimulatory molecules, CD40 and CD137, and Treg-depleting anti-CD25 antibodies showed no effect. All these data suggest that peripheral immune tolerance against the mTSHR may play a minor role, and imply the importance of central tolerance, in immune tolerance against mTSHR in mice. Additional studies on central tolerance to the mTSHR will be necessary for completely delineating the mechanisms for immune tolerance against mTSHR in mice.

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