PD-1/PD-L1, but not PD-1/PD-L2, interactions regulate the severity of experimental autoimmune encephalomyelitis

Carter, Laura; Leach, Michael W.; Azoitei, Mihai L.; Cui, Junqing; Pelker, Jeffrey W.; Jussif, Jason; Benoit, Steve; Ireland, Gretchen; Luxenberg, Deborah; Askew, G. Roger; Milarski, Kim; Groves, Christopher; Brown, Tom; Carito, Brenda; Percival, Karen; Carreño, Beatriz M.; Collins, Mary; Marušić, Suzana

doi:10.1016/j.jneuroim.2006.10.006

Cited by 172 publications

(176 citation statements)

References 54 publications

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“…PD-1-PD-L1 interaction has been suggested to play a central role in the regulation of induction and progression of autoimmune diabetes in NOD mice (42). PD-1K/K and PD-L1K/K mice developed more severe EAE than wildtype and PD-L2K/K mice (43). PD-1-PD-L1 interaction attenuates T-cell responses.…”

Section: Graves' N (%)mentioning

confidence: 99%

Association of an A/C single nucleotide polymorphism in programmed cell death-ligand 1 gene with Graves' disease in Japanese patients.

Hayashi¹,

Kouki²,

Takasu³

et al. 2008

European Journal of Endocrinology

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Objective: Programmed cell death-1 (PD-1) and its ligands (PD-L1 and PD-L2) inhibit T-cell proliferation and activation. This inhibition down-regulates the immune responses. The association of a PD-L1 polymorphism with Graves' disease (GD) was studied. Design: The association of an A/C polymorphism at position 8923 in PD-L1 intron 4 with GD was studied. Patients: The study included 327 GD patients and 192 controls, of which 252 GD patients were followed over 5-10 years. Measurements: PD-L1 intron 4 position 8923 A/C polymorphism was typed using the PCR-restriction fragment length polymorphism method. Results: The A/C genotype frequencies were significantly different between GD patients and controls. The A/C and C/C frequencies were higher in GD patients than in controls. The A/A frequencies were lower in GD patients than in controls. C-allele frequency was higher in GD patients than in controls. A total of 252 GD patients were followed over 5-10 years; 200 had discontinued antithyroid drugs (ATD) while 52 continued to take ATD. Of these 200, 176 continued to be in remission and 24 had relapsed into hyperthyroidism. Significant differences in the duration of positive TBII, positive thyroid-stimulating antibodies, and ATD treatment were noted between the patients in remission and those that had relapsed. Significant differences in the A-and C-allele frequencies were noted between the two. The C-allele frequency was higher in GD patients who did not achieve remission than in those who achieved remission.

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Section: Graves' N (%)mentioning

confidence: 99%

Association of an A/C single nucleotide polymorphism in programmed cell death-ligand 1 gene with Graves' disease in Japanese patients.

Hayashi¹,

Kouki²,

Takasu³

et al. 2008

European Journal of Endocrinology

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“…In CNS autoimmunity, genetic deletion of either B7-H1 or PD-1 renders mice more susceptible to development of EAE (24)(25)(26). B7-H1 is upregulated in inflammatory CNS lesions and critically determines local effector T cell activation, survival, and recruitment of regulatory T cells (T reg ) into the CNS, thereby limiting CNS damage (24,27).…”

mentioning

confidence: 99%

B7-H1 Selectively Controls TH17 Differentiation and Central Nervous System Autoimmunity via a Novel Non–PD-1–Mediated Pathway

Herold

Posevitz

Chudyka

et al. 2015

The Journal of Immunology

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It is currently acknowledged that TH17 cells are critically involved in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). In this article, we demonstrate that signals delivered by the coinhibitory molecule B7-homologue 1 (B7-H1) via a B7-homologue 1 mouse-IgG2aFc (B7-H1-Ig) fusion protein nearly abolish TH17, but not TH1 and TH2, differentiation via direct interaction with the T cell. These effects were equally pronounced in the absence of programmed death-1 or B7.1 and B7.2 on the T cell side, thus providing clear evidence that B7-H1 modulates T cell differentiation via a novel receptor. Mechanistically, B7-H1 interfered with early TCR-mediated signaling and cytokine-mediated induction of the TH17-determining transcription factors retinoic acid-related orphan receptor γ t and IFN regulator factor-4 in a programmed death-1 and B7-independent fashion. In an animal model of MS, active myelin oligodendrocyte glycoprotein–induced experimental autoimmune encephalomyelitis, B7-H1-Ig exhibited a significant and long-lasting effect on disease severity upon administration during the first 5 d of the priming phase, which was accompanied by reduced TH17 responses in the periphery and within the CNS. Importantly, B7-H1-Ig was even capable of interfering with T cell encephalitogenicity when interaction with the T cells occurred after priming using an adoptive transfer experimental autoimmune encephalomyelitis model. In line with this, both naive human CD4+ T cells and differentiated TH17 effector cells from MS patients were highly sensitive toward B7-H1-Ig–mediated TH17 suppression. Together, we propose the existence of a novel B7-H1–mediated immune-regulatory pathway in T cells, which selectively limits murine and human TH17 cell responses and might be therapeutically exploited to control TH17-mediated autoimmunity.

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“…PD-1 and its ligands were found to be strongly expressed on immune infiltrates in the CNS during the peak phase of EAE (9)(10)(11). In EAE studies, PD-1-deficient mice or the use of blocking antibodies that inhibit PD-1 engagement by ligands resulted in earlier disease onset, increased inflammatory infiltrates, and increased severity of clinical symptoms compared with normal disease progression (10)(11)(12)(13)(14)(15)(16). It has been demonstrated that ligand engagement of PD-1 inhibits T-cell activation, expansion, and cytokine production (17)(18)(19).…”

mentioning

confidence: 99%

“…Recently, T-helper 17 (Th17) cells were shown to be involved in EAE by producing IL-17 and GM-CSF (20,21). Two reports showed that PD-1 −/− mice mount an augmented Th17 response to EAE induction (14,16). However, the fundamental mechanisms by which PD-1 regulates antigen-specific Th17 cell differentiation, expansion, and effector function in EAE remain to be understood.…”

mentioning

confidence: 99%

Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response

Rui

Honjo

Chikuma

2013

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

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Programmed cell death 1 (PD-1) is an inhibitory coreceptor on immune cells and is essential for self-tolerance because mice genetically lacking PD-1 (PD-1 −/− ) develop spontaneous autoimmune diseases. PD-1 −/− mice are also susceptible to severe experimental autoimmune encephalomyelitis (EAE), characterized by a massive production of effector/memory T cells against myelin autoantigen, the mechanism of which is not fully understood. We found that an increased primary response of PD-1 −/− mice to heat-killed mycobacteria (HKMTB), an adjuvant for EAE, contributed to the enhanced production of T-helper 17 (Th17) cells. Splenocytes from HKMTB-immunized, lymphocyte-deficient PD-1 −/− recombination activating gene (RAG)2 −/− mice were found to drive antigen-specific Th17 cell differentiation more efficiently than splenocytes from HKMTB-immunized PD-1 +/+ RAG2 −/− mice. This result suggested PD-1's involvement in the regulation of innate immune responses. Mice reconstituted with PD-1 −/− RAG2 −/− bone marrow and PD-1 +/+ CD4 + T cells developed more severe EAE compared with the ones reconstituted with PD-1 +/+ RAG2 −/− bone marrow and PD-1 +/+ CD4 + T cells. We found that upon recognition of HKMTB, CD11b + macrophages from PD-1 −/− mice produced very high levels of IL-6, which helped promote naive CD4 + T-cell differentiation into IL-17-producing cells. We propose a model in which PD-1 negatively regulates antimycobacterial responses by suppressing innate immune cells, which in turn prevents autoreactive T-cell priming and differentiation to inflammatory effector T cells.autoimmunity | inflammation

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PD-1/PD-L1, but not PD-1/PD-L2, interactions regulate the severity of experimental autoimmune encephalomyelitis

Cited by 172 publications

References 54 publications

Association of an A/C single nucleotide polymorphism in programmed cell death-ligand 1 gene with Graves' disease in Japanese patients.

Association of an A/C single nucleotide polymorphism in programmed cell death-ligand 1 gene with Graves' disease in Japanese patients.

B7-H1 Selectively Controls TH17 Differentiation and Central Nervous System Autoimmunity via a Novel Non–PD-1–Mediated Pathway

Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response

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