T cells presenting viral antigens or autoantigens induce cytotoxic T cell anergy

Blachère, Nathalie E.; Orange, Dana E.; Santomasso, Bianca; Couture, Graeme C.; Ramirez-Montagut, Teresa; Fak, John; O’Donovan, Kevin J.; Zhong, Ruiqin; Parveen, Salina; Frank, Mayu O.; Moore, Michael J.; Darnell, Robert B.

doi:10.1172/jci.insight.96173

Cited by 4 publications

(5 citation statements)

References 29 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Albert et al revealed that patients with HLA‐A2.1‐positive PCD who presented with anti‐Yo antibodies had CD8 + T cells with CTL activity against a peptide of Yo protein (cerebellar degeneration‐related protein 2 [CDR2]) 12 . Recently, they showed that CDR2 was expressed in T cells of the peripheral blood in physiological conditions that may affect the immunological tolerance of CDR2 expressing tumor rejection in PCD 35 . Extremely few patients with gynecological or breast cancer present with neurological symptoms including PCD.…”

Section: Discussionmentioning

confidence: 99%

“…12 Recently, they showed that CDR2 was expressed in T cells of the peripheral blood in physiological conditions that may affect the immunological tolerance of CDR2 expressing tumor rejection in PCD. 35 Extremely few patients with gynecological or breast cancer present with neurological symptoms including PCD. In the development of neurological disturbance, this tolerance might be disrupted with the dysregulation of regulatory T cells or other cell types.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Trial of cytotoxic T cell induction in mice as an ex vivo model of paraneoplastic neurologic syndrome with anti‐Hu antibodies

Tanaka

Tani

Ogawa

et al. 2022

Clinical & Exp Neuroim

View full text Add to dashboard Cite

The pathogenesis of neuronal damage in anti-Hu-antibody-positive paraneoplastic neurologic syndrome (Hu-PNS) is thought to be mediated by cytotoxic T lymphocyte (CTL). However, there is no direct evidence showing that antigen-specific T cells are the effector against neurons. Antigen-specific CTL-mediated cell death has been observed in cancer immunology, but not as a neurological disease model. The CTLmediated etiology in PNS should be confirmed using in vivo model systems in the future. Herein, we present an ex vivo model of antigen-specific CTL against cultured neurons. A previous study showed the CTL activity of CD8 + T cells taken from the peripheral blood of patients with Hu-antibody-positive PNS against Hu-proteinderived-peptide-expressing autologous fibroblasts. Results revealed that the HuD peptide, which can bind to major histocompatibility complex (MHC) class I of Balb/c mice, stimulated CD8 + T cells collected from mice immunized with peptide-bound self-activated dendritic cells with murine CD40 ligand-transduced adenovirus vectors (AdmCD40L). Moreover, CTL activity against autologous neurons in culture was observed. Hence, this result could be used in the development of an in vivo model of CTL-induced neurological disorders, which can help in further understanding the pathogenesis of PNS.cytotoxic T cells, Hu-antibody-positive paraneoplastic neurologic syndrome, induction of CTL in mice, killing of cultured neurons | INTRODUCTIONSeveral characteristic autoantibodies against specific neuronal and tumor tissues have been observed in different types of paraneoplastic neurologic syndrome (PNS). 1-5 Among them, anti-Hu antibodies are detected in patients with limbic encephalitis or subacute sensory neuronopathy or other symptoms associated with small-cell lung cancer. Meanwhile, anti-Yo antibodies is commonly found in women with subacute cerebellar symptoms associated with gynecological or breast cancer. These antibodies are highly characteristic in these groups of patients and are detected at the early stages of neurological disease. Moreover, they bind to relevant tumors and neuronal tissues, which indicate a close relationship with the pathogenesis of paraneoplastic neurologic syndromes. Several studies have assessed the direct role of antibodies in neuronal damage. 6 However, the results were controversial, and whether these antibodies, which recognize intracellular antigens such as anti-Hu and anti-Yo, damage the neurons remains unclear. 7-10 By contrast, there is increasing evidence showing that T lymphocytes are the effector of neuronal damage. [11][12][13][14][15][16] At the early stages of paraneoplastic cerebellar degeneration (PCD) with anti-Yo-or anti-Hu-positive PNS, the CSF contains several mononuclear cells. Inflammatory cells, mainly CD8-positive T lymphocytes, infiltrate the tumor and nervous tissues, thereby causing

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Trial of cytotoxic T cell induction in mice as an ex vivo model of paraneoplastic neurologic syndrome with anti‐Hu antibodies

Tanaka

Tani

Ogawa

et al. 2022

Clinical & Exp Neuroim

View full text Add to dashboard Cite

show abstract

“…Red blood cells were removed by hypotonic lysis. Quadruplicate ELISpot wells containing mononuclear cells, were supplemented with the IAV NP peptide (366-374; ASNENMETM) (2 μg/ml), to serve as a H2-D b -restricted epitope from the Influenza A/PR/8/34 nucleoprotein ( 27 , 28 ). As a control, medium without added IAV peptide was used.…”

Section: Methodsmentioning

confidence: 99%

Noninvasive Immuno-PET Imaging of CD8+ T Cell Behavior in Influenza A Virus-Infected Mice

Rothlauf

Pishesha

et al. 2021

Front. Immunol.

View full text Add to dashboard Cite

Immuno-positron emission tomography (immuno-PET) is a noninvasive imaging method that enables tracking of immune cells in living animals. We used a nanobody that recognizes mouse CD8α and labeled it with 89Zr to image mouse CD8+ T cells in the course of an infection with influenza A virus (IAV). The CD8+ signal showed a strong increase in the mediastinal lymph node (MLN) and thymus as early as 4 days post-infection (dpi), and as early as 6 dpi in the lungs. Over the course of the infection, CD8+ T cells were at first distributed diffusely throughout the lungs and then accumulated more selectively in specific regions of the lungs. These distributions correlated with morbidity as mice reached the peak of weight loss over this interval. CD8+ T cells obtained from control or IAV-infected mice showed a difference in their distribution and migration when comparing their fate upon labeling ex vivo with 89Zr-labeled anti-CD8α nanobody and transfer into infected versus control animals. CD8+ T cells from infected mice, upon transfer, appear to be trained to persist in the lungs, even of uninfected mice. Immuno-PET imaging thus allows noninvasive, dynamic monitoring of the immune response to infectious agents in living animals.

show abstract

“…Therefore, the mere expression of CDR2/CDR2L by tumor cells is insufficient to trigger autoimmunity against Purkinje cells. The low incidence of PCD may also be linked to the lymphocyte expression of CDR2 (118).…”

Section: Cdr2/cdr2l Protein Expression In Tumor and T Cellsmentioning

confidence: 99%

Immunological Bases of Paraneoplastic Cerebellar Degeneration and Therapeutic Implications

2020

View full text Add to dashboard Cite

Paraneoplastic cerebellar degeneration (PCD) is a rare immune-mediated disease that develops mostly in the setting of neoplasia and offers a unique prospect to explore the interplay between tumor immunity and autoimmunity. In PCD, the deleterious adaptive immune response targets self-antigens aberrantly expressed by tumor cells, mostly gynecological cancers, and physiologically expressed by the Purkinje neurons of the cerebellum. Highly specific anti-neuronal antibodies in the serum and cerebrospinal fluid represent key diagnostic biomarkers of PCD. Some anti-neuronal antibodies such as anti-Yo autoantibodies (recognizing the CDR2/CDR2L proteins) are only associated with PCD. Other anti-neuronal antibodies, such as anti-Hu, anti-Ri, and anti-Ma2, are detected in patients with PCD or other types of paraneoplastic neurological manifestations. Importantly, these autoantibodies cannot transfer disease and evidence for a pathogenic role of autoreactive T cells is accumulating. However, the precise mechanisms responsible for disruption of self-tolerance to neuronal self-antigens in the cancer setting and the pathways involved in pathogenesis within the cerebellum remain to be fully deciphered. Although the occurrence of PCD is rare, the risk for such severe complication may increase with wider use of cancer immunotherapy, notably immune checkpoint blockade. Here, we review recent literature pertaining to the pathophysiology of PCD and propose an immune scheme underlying this disabling disease. Additionally, based on observations from patients' samples and on the pre-clinical model we recently developed, we discuss potential therapeutic strategies that could blunt this cerebellum-specific autoimmune disease.

show abstract

T cells presenting viral antigens or autoantigens induce cytotoxic T cell anergy

Cited by 4 publications

References 29 publications

Trial of cytotoxic T cell induction in mice as an ex vivo model of paraneoplastic neurologic syndrome with anti‐Hu antibodies

Trial of cytotoxic T cell induction in mice as an ex vivo model of paraneoplastic neurologic syndrome with anti‐Hu antibodies

Noninvasive Immuno-PET Imaging of CD8+ T Cell Behavior in Influenza A Virus-Infected Mice

Immunological Bases of Paraneoplastic Cerebellar Degeneration and Therapeutic Implications

Contact Info

Product

Resources

About