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; Hayashi, Hiroshi; Honjo, Tasuku; Okazaki, Taku

doi:10.1093/intimm/dxq026

Cited by 225 publications

(174 citation statements)

References 37 publications

Supporting

Mentioning

164

Contrasting

Unclassified

Order By: Relevance

“…However, thymectomy can cause other effects such as severe lymphopenia, which can support autoimmunity. The PD-1-deficient MRL strain of mice showed rapid and fatal autoimmune myocarditis for undefined reasons (35). A mild functional deficiency of Treg cells reported in this strain (36) FoxP3 expression on Tregs might have caused excessive activation of conventional T cells.…”

Section: Discussionmentioning

confidence: 88%

See 1 more Smart Citation

Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model

Zhang

Chikuma

Hori

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

146

108

View full text Add to dashboard Cite

PD-1 (programmed-death 1), an immune-inhibitory receptor required for immune self-tolerance whose deficiency causes autoimmunity with variable severity and tissue specificity depending on other genetic factors, is expressed on activated T cells, including the transcription factor FoxP3 + Treg cells known to play critical roles in maintaining immune tolerance. However, whether PD-1 expression by the Treg cells is required for their immune regulatory function, especially in autoimmune settings, is still unclear. We found that mice with partial FoxP3 insufficiency developed early-onset lympho-proliferation and lethal autoimmune pancreatitis only when PD-1 is absent. The autoimmune phenotype was rescued by the transfer of FoxP3-sufficient T cells, regardless of whether they were derived from WT or PD-1-deficient mice, indicating that Treg cells dominantly protect against development of spontaneous autoimmunity without intrinsic expression of PD-1. The absence of PD-1 combined with partial FoxP3 insufficiency, however, led to generation of ex-FoxP3 T cells with proinflammatory properties and expansion of effector/memory T cells that contributed to the autoimmune destruction of target tissues. Altogether, the results suggest that PD-1 and FoxP3 work collaboratively in maintaining immune tolerance mostly through nonoverlapping pathways. Thus, PD-1 is modulating the activation threshold and maintaining the balance between regulatory and effector T cells, whereas FoxP3 is sufficient for dominant regulation through maintaining the integrity of the Treg function. We suggest that genetic or environmental factors that even moderately affect the expression of both PD-1 and FoxP3 can cause life-threatening autoimmune diseases by disrupting the T-cell homeostasis.immune tolerance | autoimmunity | T lymphocytes | regulatory T cell | PD-1

show abstract

Section: Discussionmentioning

confidence: 88%

“…PD-1-deficient mice developed autoimmune phenotypes, which were strainspecific (12,22,34,35). In the C57BL/6 background, PD-1 deficiency induced arthritis and nephritis (22), whereas in the BALB/c background, deficiency induced mostly myocarditis and gastritis (12,34).…”

Section: Discussionmentioning

confidence: 99%

Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model

Zhang

Chikuma

Hori

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

146

108

View full text Add to dashboard Cite

show abstract

“…Engagement of PD-1 by its ligands, PD-L1 and PD-L2, induces an inhibitory signal resulting in reduced T-cell proliferation, cytokine production, and cytotoxic activity (4,5). PD-1 deletion in mice can lead to autoimmunity (6,7), most notably when bred onto backgrounds of autoimmune-susceptible mouse strains (8). Elevated PD-1 expression on T cells, observed during chronic viral infections in humans and mice, is associated with reduced Tcell functionality or "exhaustion."…”

Section: Introductionmentioning

confidence: 99%

In VitroCharacterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, andIn VivoToxicology in Non-Human Primates

Wang

Thudium

Han

et al. 2014

Cancer Immunology Research

540

405

View full text Add to dashboard Cite

The programmed death-1 (PD-1) receptor serves as an immunologic checkpoint, limiting bystander tissue damage and preventing the development of autoimmunity during inflammatory responses. PD-1 is expressed by activated T cells and downmodulates T-cell effector functions upon binding to its ligands, PD-L1 and PD-L2, on antigen-presenting cells. In patients with cancer, the expression of PD-1 on tumor-infiltrating lymphocytes and its interaction with the ligands on tumor and immune cells in the tumor microenvironment undermine antitumor immunity and support its rationale for PD-1 blockade in cancer immunotherapy. This report details the development and characterization of nivolumab, a fully human IgG4 (S228P) anti-PD-1 receptor-blocking monoclonal antibody. Nivolumab binds to PD-1 with high affinity and specificity, and effectively inhibits the interaction between PD-1 and its ligands. In vitro assays demonstrated the ability of nivolumab to potently enhance T-cell responses and cytokine production in the mixed lymphocyte reaction and superantigen or cytomegalovirus stimulation assays. No in vitro antibody-dependent cell-mediated or complement-dependent cytotoxicity was observed with the use of nivolumab and activated T cells as targets. Nivolumab treatment did not induce adverse immune-related events when given to cynomolgus macaques at high concentrations, independent of circulating anti-nivolumab antibodies where observed. These data provide a comprehensive preclinical characterization of nivolumab, for which antitumor activity and safety have been demonstrated in human clinical trials in various solid tumors. Cancer Immunol Res; 2(9); 846-56. Ó2014 AACR.

show abstract

“…PD-1 ligation induces functional T cell anergy through the inhibition of T cellautonomous IL-2 production in vivo (7). Genetically manipulated PD-1 knockout mice develop spontaneous autoimmune diseases against various tissues, depending on their background (8)(9)(10)(11)(12). In contrast, PD-1-deficient mice are resistant to viral infections (13) and neoplasia (14,15).…”

mentioning

confidence: 99%

IFN-α Directly Promotes Programmed Cell Death-1 Transcription and Limits the Duration of T Cell-Mediated Immunity

Terawaki

Chikuma

Shibayama

et al. 2011

The Journal of Immunology

Self Cite

306

220

View full text Add to dashboard Cite

Programmed cell death-1 (PD-1) is an inhibitory coreceptor for T lymphocytes that provides feedback inhibition of T cell activation. Although PD-1’s expression on T cells is known to be activation dependent, the factors that determine the timing, intensity, and duration of PD-1 expression in immune reactions are not fully understood. To address this question, we performed a fine mapping analysis of a conserved 5′-flanking region of the PD-1 gene and identified a putative IFN stimulation response element, which was responsible for PD-1 transcription in the 2B4.11 T cell line. Consistent with this finding, activation by IFN-α enhanced both the induction and maintenance of PD-1 expression on TCR-engaged primary mouse T cells through an association IFN-responsive factor 9 (IRF9) to the IFN stimulation response element. Furthermore, PD-1 expression on Ag-specific CD8+ T cells was augmented by IFN-α in vivo. We propose that strong innate inflammatory responses promote primary T cell activation and their differentiation into effector cells, but also cause an attenuated T cell response in sustained immune reactions, at least partially through type I IFN-mediated PD-1 transcription. Based on this idea, we demonstrate that IFN-α administration in combination with PD-1 blockade in tumor-bearing mice effectively augments the antitumor immunity, and we propose this as a novel and rational approach for cancer immunotherapy.

show abstract

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

Cited by 225 publications

References 37 publications

Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model

Nonoverlapping roles of PD-1 and FoxP3 in maintaining immune tolerance in a novel autoimmune pancreatitis mouse model

In VitroCharacterization of the Anti-PD-1 Antibody Nivolumab, BMS-936558, andIn VivoToxicology in Non-Human Primates

IFN-α Directly Promotes Programmed Cell Death-1 Transcription and Limits the Duration of T Cell-Mediated Immunity

Contact Info

Product

Resources

About