Accelerated Course of Experimental Autoimmune Encephalomyelitis in PD-1-Deficient Central Nervous System Myelin Mutants

Kroner, Antje; Schwab, Nicholas; Ip, Chi Wang; Ortler, Sonja; Göbel, Kerstin; Nave, Klaus‐Armin; Mäurer, Mathias; Martini, Rudolf; Wiendl, Heinz

doi:10.2353/ajpath.2009.081012

Cited by 42 publications

(38 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…injections of pertussis toxin (PTX), which is assumed to induce a strong innate immune response leading to MOG-specific T-cell priming. In agreement with previous reports (12,14), the induction of EAE with this treatment resulted in accelerated disease progression in PD-1 −/− mice, characterized by earlier disease onset and an earlier peak in disease activity (Fig. 1A).…”

Section: Resultssupporting

confidence: 80%

“…It has been demonstrated that ligand engagement of PD-1 inhibits T-cell activation, expansion, and cytokine production (17)(18)(19). Similarly, in EAE, PD-1 signaling in CNS-specific helper T cells may inhibit their expansion and secretion of inflammatory cytokines (10)(11)(12). Recently, T-helper 17 (Th17) cells were shown to be involved in EAE by producing IL-17 and GM-CSF (20,21).…”

mentioning

confidence: 99%

“…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%

See 2 more Smart Citations

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.

View full text Add to dashboard Cite

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

show abstract

Section: Resultssupporting

confidence: 80%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 1 more Smart Citation

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.

View full text Add to dashboard Cite

show abstract

“…B7-H1 is constitutively expressed on different immune cells and can be inducibly expressed on many parenchymal cells (14)(15)(16)(17)(18) is crucially involved in maintenance of immunological tolerance (19,20). PD-1 has been identified as the canonical receptor for B7-H1 and is inducibly expressed on activated lymphocytes (21).…”

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…With regard to the first aspect, we addressed the impact of lack of B7-H1 on either APCs or CD4 + T cells by performing coculture assays of MOGspecific B cells and MOG-specific CD4 + T cells in the presence of recombinant MOG protein and observed that B7-H1 was completely dispensable on antigen-presenting B cells but augmented CD4 + T-cell expansion and effector functions when lacking on the T-cell side. The B7-H1-PD-1 pathway has received major attention over the last years as a key component of the B7-homologs involved in the regulation of immune tolerance, tumor surveillance, and autoimmunity (18,(23)(24)(25). Despite its well-known role in immune regulation by APCs via interaction with its canonical receptor PD-1 on T cells, only a few studies so far have investigated the relevance of B7-H1 on T cells: Talay et al observed that expression of B7-H1 was required for T-cell-mediated conditioning of dendritic cell maturation in the context of infections (26).…”

Section: Discussionmentioning

confidence: 99%

B7-H1 shapes T-cell–mediated brain endothelial cell dysfunction and regional encephalitogenicity in spontaneous CNS autoimmunity

Klotz

Kuzmanov

Hucke

et al. 2016

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

Self Cite

View full text Add to dashboard Cite

Molecular mechanisms that determine lesion localization or phenotype variation in multiple sclerosis are mostly unidentified. Although transmigration of activated encephalitogenic T cells across the bloodbrain barrier (BBB) is a crucial step in the disease pathogenesis of CNS autoimmunity, the consequences on brain endothelial barrier integrity upon interaction with such T cells and subsequent lesion formation and distribution are largely unknown. We made use of a transgenic spontaneous mouse model of CNS autoimmunity characterized by inflammatory demyelinating lesions confined to optic nerves and spinal cord (OSE mice). Genetic ablation of a single immune-regulatory molecule in this model [i.e., B7-homolog 1 (B7-H1, PD-L1)] not only significantly increased incidence of spontaneous CNS autoimmunity and aggravated disease course, especially in the later stages of disease, but also importantly resulted in encephalitogenic T-cell infiltration and lesion formation in normally unaffected brain regions, such as the cerebrum and cerebellum. Interestingly, B7-H1 ablation on myelin oligodendrocyte glycoprotein-specific CD4 + T cells, but not on antigen-presenting cells, amplified T-cell effector functions, such as IFN-γ and granzyme B production. Therefore, these T cells were rendered more capable of eliciting cell contact-dependent brain endothelial cell dysfunction and increased barrier permeability in an in vitro model of the BBB. Our findings suggest that a single immuneregulatory molecule on T cells can be ultimately responsible for localized BBB breakdown, and thus substantial changes in lesion topography in the context of CNS autoimmunity.neuroinflammation | multiple sclerosis | spontaneous EAE | CNS lesion distribution | blood-brain barrier M ultiple sclerosis (MS) is the most common chronic inflammatory demyelinating disease of the CNS. Disease pathogenesis is initiated by peripheral activation of autoimmune T lymphocytes by yet unknown mechanisms, followed by T-cell expansion and subsequent migration across the complex structure of the blood-brain barrier (BBB). Within the CNS, entry of this first wave of T cells elicits recruitment of other immune cells, which together evoke a local inflammatory process ultimately resulting in demyelination, as well as axonal and neuronal damage (1). Several histological MS subtypes have been described with regard to lesion distribution and cellular composition (2). The reasons underlying distinct lesion development at different anatomical sites still remain however largely elusive: Some authors have proposed that the nature and expression pattern of the target autoantigen might play a role (3, 4). Others have observed an influence of the HLA complex and its role in shaping antigen presentation, thus suggesting that T-cell antigen specificity might impact the location of inflammation (5). Additionally, T-cell polarization into distinct T helper subtypes, as well as their expression pattern of chemokine receptors and adhesion molecules, has been implicated in determining the lo...

show abstract

Accelerated Course of Experimental Autoimmune Encephalomyelitis in PD-1-Deficient Central Nervous System Myelin Mutants

Cited by 42 publications

References 41 publications

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

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

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

B7-H1 shapes T-cell–mediated brain endothelial cell dysfunction and regional encephalitogenicity in spontaneous CNS autoimmunity

Contact Info

Product

Resources

About