Effective and selective immune surveillance of the brain by MHC class I‐restricted cytotoxic T lymphocytes

Cabarrocas, Julie; Bauer, Jan; Piaggio, Eliane; Liblau, Roland; Lassmann, Hans

doi:10.1002/eji.200323492

Cited by 109 publications

(97 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In the resulting double-transgenic Orex-HA mice, the expression of HA of an H1N1 influenza virus, which is otherwise prevented by an upstream floxed Stop cassette, was induced because of the expression of the Cre recombinase specifically in orexin + neurons. The (BALB/cJ × C57BL/6J) F1-CL4-TCR and F1-6.5-TCR mice have been described (43,44). To perform two-photon laser microscopy experiments, we generated Orex-HA-ZsGreen triple-transgenic mice by the cross of C57BL/6J Orex-Cre mice, C57BL/6J.Cg-Gt(ROSA)26 Sortm6(CAG-ZsGreen1)Hze (The Jackson Laboratory) (45), and BALB/cJ-Rosa26 tm(HA)1Lib…”

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

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

show abstract

“…HA-specific Tc1 cells were generated as described and routinely contained Ͼ98% pure CD8 ϩ CD3 ϩ V␤8.2 ϩ T cells (13). GFP transduction of the HAspecific Tc1 cells was performed using the pLGFPSN retroviral vector and the GPϩE-86 packaging cell line.…”

Section: In Vitro Differentiation Gfp Transduction Adoptive Transfementioning

confidence: 99%

Cutting Edge: Multiple Sclerosis-Like Lesions Induced by Effector CD8 T Cells Recognizing a Sequestered Antigen on Oligodendrocytes

Saxena

Bauer

Scheikl

et al. 2008

The Journal of Immunology

Self Cite

125

109

View full text Add to dashboard Cite

CD8 T cells are emerging as important players in multiple sclerosis (MS) pathogenesis, although their direct contribution to tissue damage is still debated. To assess whether autoreactive CD8 T cells can contribute to the pronounced loss of oligodendrocytes observed in MS plaques, we generated mice in which the model Ag influenza hemagglutinin is selectively expressed in oligodendrocytes. Transfer of preactivated hemagglutinin-specific CD8 T cells led to inflammatory lesions in the optic nerve, spinal cord, and brain. These lesions, associating CD8 T cell infiltration with focal loss of oligodendrocytes, demyelination, and microglia activation, were very reminiscent of active MS lesions. Thus, our study demonstrates the potential of CD8 T cells to induce oligodendrocyte lysis in vivo as a likely consequence of direct Ag-recognition. These results provide new insights with regard to CNS tissue damage mediated by CD8 T cells and for understanding the role of CD8 T cells in MS.

show abstract

“…Immunotherapy for glioma is an attractive approach because activated, antitumor immune cells may have the potential to migrate into the CNS and selectively destroy malignant cells that have infiltrated normal CNS tissues (3)(4)(5)(6). Dedicated to development of novel immunotherapy approaches for glioma, we have addressed our major focus on identification and characterization of novel HLA-A2-restricted CTL epitopes derived from glioma-associated Ags (GAAs) 3 such as IL-13R␣2 (7,8) and a receptor-tyrosine kinase EphA2 (9). A novel vaccine trial using synthetic peptides encoding these GAA-derived CTL epitopes and a TLR-3 ligand poly-ICLC is presently underway (10).…”

Section: Inhibition Of Stat3 Promotes the Efficacy Of Adoptive Transfmentioning

confidence: 99%

Inhibition of STAT3 Promotes the Efficacy of Adoptive Transfer Therapy Using Type-1 CTLs by Modulation of the Immunological Microenvironment in a Murine Intracranial Glioma

Fujita

Zhu

Sasaki

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

A variety of cancers, including malignant gliomas, show aberrant activation of STAT3, which plays a pivotal role in negative regulation of antitumor immunity. We hypothesized that inhibition of STAT3 signals would improve the efficacy of T cell adoptive transfer therapy by reversal of STAT3-induced immunosuppression in a murine GL261 intracranial glioma model. In vitro treatment of GL261 cells with JSI-124, a STAT3 inhibitor, reversed highly phosphorylated status of STAT3. Systemic i.p. administration of JSI-124 in glioma-bearing immunocompetent mice, but not athymic mice, resulted in prolonged survival, suggesting a role of adaptive immunity in the antitumor effect. Furthermore, JSI-124 promoted maturation of tumor-infiltrating CD11c+ dendritic cells and activation of tumor-conditioned cytotoxic T cells, enhanced dendritic cells and GL261 production of CXCL-10, a critical chemokine for attraction of Tc1 cells. When i.p. JSI-124 administration was combined with i.v. transfer of Pmel-I mouse-derived type-1 CTLs (Tc1), glioma-bearing mice exhibited prolonged survival compared with i.p. JSI-124 or i.v. Tc1 therapy alone. Flow cytometric analyses of brain infiltrating lymphocytes revealed that JSI-124-treatment enhanced the tumor-homing of i.v. transferred Tc1 cells in a CXCL-10-dependent fashion. Systemic JSI-124 administration also up-regulated serum IL-15 levels, and promoted the persistence of transferred Tc1 in the host. These data suggest that systemic inhibition of STAT3 signaling can reverse the suppressive immunological environment of intracranial tumor bearing mice both systemically and locally, thereby promoting the efficacy of adoptive transfer therapy with Tc1.

show abstract

Effective and selective immune surveillance of the brain by MHC class I‐restricted cytotoxic T lymphocytes

Cited by 109 publications

References 51 publications

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

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

Cutting Edge: Multiple Sclerosis-Like Lesions Induced by Effector CD8 T Cells Recognizing a Sequestered Antigen on Oligodendrocytes

Inhibition of STAT3 Promotes the Efficacy of Adoptive Transfer Therapy Using Type-1 CTLs by Modulation of the Immunological Microenvironment in a Murine Intracranial Glioma

Contact Info

Product

Resources

About