Cutting Edge: Neuronal Recognition by CD8 T Cells Elicits Central Diabetes Insipidus

Scheikl, Tanja; Pignolet, Béatrice; Dalard, Cécile; Desbois, Sabine; Raison, Danièle; Yamazaki, Masanori; Saoudi, Abdelhadi; Bauer, Jan; Lassmann, Hans; Hardin‐Pouzet, Hélène; Liblau, Roland

doi:10.4049/jimmunol.1102998

Cited by 26 publications

(26 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Somatic upregulation of MHC I on neurons may also mark these cells for elimination by anti‐neuronal T cells, leading to loss of neurons in otherwise normal appearing gray matter. Indeed several studies have shown that targeting neoantigens to CNS neuronal subsets results in rapid clearance by antigen‐specific CD8 + T cells 15, 69, 70, 71. Finally, anterograde transport of MHC class I molecules into the distal axon makes these molecules available near the site of inflammation, where they may increase vulnerability to attack by autoreactive anti‐axonal CD8 + T cells 10.…”

Section: Discussionmentioning

confidence: 99%

Retrograde interferon‐gamma signaling induces major histocompatibility class I expression in human‐induced pluripotent stem cell‐derived neurons

Clarkson

Patel

LaFrance‐Corey

et al. 2017

Ann Clin Transl Neurol

View full text Add to dashboard Cite

ObjectiveInjury‐associated axon‐intrinsic signals are thought to underlie pathogenesis and progression in many neuroinflammatory and neurodegenerative diseases, including multiple sclerosis (MS). Retrograde interferon gamma (IFN γ) signals are known to induce expression of major histocompatibility class I (MHC I) genes in murine axons, thereby increasing the susceptibility of these axons to attack by antigen‐specific CD8+ T cells. We sought to determine whether the same is true in human neurons.MethodsA novel microisolation chamber design was used to physically isolate and manipulate axons from human skin fibroblast‐derived induced pluripotent stem cell (iPSC)‐derived neuron‐enriched neural aggregates. Fluorescent retrobeads were used to assess the fraction of neurons with projections to the distal chamber. Axons were treated with IFN γ for 72 h and expression of MHC class I and antigen presentation genes were evaluated by RT‐PCR and immunofluorescence.ResultsHuman iPSC‐derived neural stem cells maintained as 3D aggregate cultures in the cell body chamber of polymer microisolation chambers extended dense axonal projections into the fluidically isolated distal chamber. Treatment of these axons with IFN γ resulted in upregulation of MHC class I and antigen processing genes in the neuron cell bodies. IFN γ‐induced MHC class I molecules were also anterogradely transported into the distal axon.InterpretationThese results provide conclusive evidence that human axons are competent to express MHC class I molecules, suggesting that inflammatory factors enriched in demyelinated lesions may render axons vulnerable to attack by autoreactive CD8+ T cells in patients with MS. Future work will be aimed at identifying pathogenic anti‐axonal T cells in these patients.

show abstract

Section: Discussionmentioning

confidence: 99%

Retrograde interferon‐gamma signaling induces major histocompatibility class I expression in human‐induced pluripotent stem cell‐derived neurons

Clarkson

Patel

LaFrance‐Corey

et al. 2017

Ann Clin Transl Neurol

View full text Add to dashboard Cite

show abstract

“…T-Cell Differentiation and T-Cell Transfer. HA-specific CD8 + CTL and HA-specific CD4+ Th1 were generated from F1 CL4-TCR mice and F1 6.5-TCR mice, respectively, as described (46,47 Histopathology. Tissues were fixed in 4% (wt/vol) paraformaldehyde, conserved in 70% (vol/vol) ethanol, and embedded in paraffin.…”

Section: Methodsmentioning

confidence: 99%

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

Bernard‐Valnet

Yshii

Quériault

et al. 2016

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

Self Cite

116

View full text Add to dashboard Cite

Narcolepsy with cataplexy is a rare and severe sleep disorder caused by the destruction of orexinergic neurons in the lateral hypothalamus. The genetic and environmental factors associated with narcolepsy, together with serologic data, collectively point to an autoimmune origin. The current animal models of narcolepsy, based on either disruption of the orexinergic neurotransmission or neurons, do not allow study of the potential autoimmune etiology. Here, we sought to generate a mouse model that allows deciphering of the immune mechanisms leading to orexin + neuron loss and narcolepsy development. We generated mice expressing the hemagglutinin (HA) as a "neo-self-antigen" specifically in hypothalamic orexin + neurons (called Orex-HA), which were transferred with effector neo-self-antigen-specific T cells to assess whether an autoimmune process could be at play in narcolepsy. Given the tight association of narcolepsy with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, we first tested the pathogenic contribution of CD4 Th1 cells. Although these T cells readily infiltrated the hypothalamus and triggered local inflammation, they did not elicit the loss of orexin + neurons or clinical manifestations of narcolepsy. In contrast, the transfer of cytotoxic CD8 T cells (CTLs) led to both T-cell infiltration and specific destruction of orexin + neurons. This phenotype was further aggravated upon repeated injections of CTLs. In situ, CTLs interacted directly with MHC class I-expressing orexin + neurons, resulting in cytolytic granule polarization toward neurons. Finally, drastic neuronal loss caused manifestations mimicking human narcolepsy, such as cataplexy and sleep attacks. This work demonstrates the potential role of CTLs as final effectors of the immunopathological process in narcolepsy.arcolepsy with cataplexy, referred to as type 1 narcolepsy (T1N), is a rare and chronic neurological disease characterized by excessive daytime sleepiness, sudden loss of muscle tone triggered by emotions (cataplexy), sleep paralysis, hypnagogic hallucinations, and fragmented nocturnal sleep (1). T1N is caused by a defective neurotransmission by the orexin/hypocretin neuropeptide and is associated with a selective and almost complete loss (85-100%) of orexinergic neurons in the hypothalamus (2, 3). The mechanisms leading to this neuronal loss are not yet elucidated, although current evidence points to an autoimmune process. Indeed, T1N is tightly associated with the human leukocyte antigen (HLA) HLA-DQB1*06:02 allele, carried by 98.4% of patients vs. 17.7% of the general European population (4). An independent association with HLA class I alleles was recently revealed in two independent studies (5, 6). Additionally, an association with polymorphisms in the T-cell receptor (TCR) α chain locus was found and replicated (7,8). Moreover, autoantibodies recognizing different antigenic targets expressed in the central nervous system (CNS) have been identified in the serum and cerebrospinal fluid (CSF) of narcoleptic patients (9-11)....

show abstract

“…27 Interestingly, significant weight loss was observed in CamK-HA mice implanted with 4T1-HA tumor following transfer of na€ ıve HA-specific CD4C T cells and CD8C T cells. Seventy two percent of the CamK-HA animals showed over 5% loss of their initial weight (Fig 2A).…”

Section: Resultsmentioning

confidence: 99%

CD4+ and CD8+ T cells are both needed to induce paraneoplastic neurological disease in a mouse model

et al. 2017

Self Cite

View full text Add to dashboard Cite

Paraneoplastic neurological disorders (PNDs) are rare human autoimmune diseases that mostly affect the central nervous system (CNS). They are triggered by an efficient immune response against a neural selfantigen that is ectopically expressed in neoplastic tumors. Due to this shared antigenic expression, the immune system reacts not only to tumor cells but also to neural cells resulting in neurological damage. Growing data point to a major role of cell-mediated immunity in PNDs associated to autoantibodies against intracellular proteins. However, its precise contribution in the pathogenesis remains unclear. In this context, our study aimed at investigating the impact of anti-tumor cellular immune responses in the development of PND. To this end, we developed an animal model mimicking PND. We used a tumor cell line expressing the hemagglutinin (HA) of influenza virus to induce an anti-tumor response in CamK-HA mice, which express HA in CNS neurons. To promote and track the T cell response against the HA antigen, na€ ıve HA-specific CD8C and/or CD4C T cells, originating from TCR-transgenic animals, were transferred into these mice. We demonstrate that HA-expressing tumors, but not control tumors, induce in vivo activation, proliferation and differentiation of na€ ıve HA-specific CD4C and CD8C T cells into effector cells. Moreover, both T cell subsets were needed to control tumor growth and induce CNS inflammation in CamK-HA mice. Thus, this new mouse model provides further insight into the cellular mechanisms whereby a potent anti-tumor immunity triggers a cancer-associated autoimmune disease, and may therefore help to develop new therapeutic strategies against PND.

show abstract

Cutting Edge: Neuronal Recognition by CD8 T Cells Elicits Central Diabetes Insipidus

Cited by 26 publications

References 17 publications

Retrograde interferon‐gamma signaling induces major histocompatibility class I expression in human‐induced pluripotent stem cell‐derived neurons

Retrograde interferon‐gamma signaling induces major histocompatibility class I expression in human‐induced pluripotent stem cell‐derived neurons

CD8 T cell-mediated killing of orexinergic neurons induces a narcolepsy-like phenotype in mice

CD4+ and CD8+ T cells are both needed to induce paraneoplastic neurological disease in a mouse model

Contact Info

Product

Resources

About