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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2020

Open Access 01-12-2020 | Multiple Sclerosis | Research

c-Met is expressed by highly autoreactive encephalitogenic CD8+ cells

Authors: Mahdia Benkhoucha, Isis Senoner, Patrice H. Lalive

Published in: Journal of Neuroinflammation | Issue 1/2020

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Abstract

Background

CD8+ T lymphocytes are critical mediators of neuroinflammatory diseases. Understanding the mechanisms that govern the function of this T cell population is crucial to better understanding central nervous system autoimmune disease pathology. We recently identified a novel population of highly cytotoxic c-Met-expressing CD8+ T lymphocytes and found that hepatocyte growth factor (HGF) limits effective murine cytotoxic T cell responses in cancer models. Here, we examined the role of c-Met-expressing CD8+ T cells by using a MOG35–55 T cell-mediated EAE model.

Methods

Mice were subcutaneously immunized with myelin oligodendrocyte glycoprotein peptide (MOG)35–55 in complete Freund’s adjuvant (CFA). Peripheral and CNS inflammation was evaluated at peak disease and chronic phase, and c-Met expression by CD8 was evaluated by flow cytometry and immunofluorescence. Molecular, cellular, and killing function analysis were performed by real-time PCR, ELISA, flow cytometry, and killing assay.

Results

In the present study, we observed that a fraction of murine effector CD8+ T cells expressed c-Met receptor (c-Met+CD8+) in an experimental autoimmune encephalitis (EAE) model. Phenotypic and functional analysis of c-Met+CD8+ T cells revealed that they recognize the encephalitogenic epitope myelin oligodendrocyte glycoprotein37–50. We demonstrated that this T cell population produces higher levels of interferon-γ and granzyme B ex vivo and that HGF directly restrains the cytolytic function of c-Met+CD8+ T cells in cell-mediated cytotoxicity reactions

Conclusions

Altogether, our findings suggest that the HGF/c-Met pathway could be exploited to modulate CD8+ T cell-mediated neuroinflammation.
Appendix
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Literature
1.
Booss J, Esiri MM, Tourtellotte WW, Mason DY. Immunohistological analysis of T lymphocyte subsets in the central nervous system in chronic progressive multiple sclerosis. J Neurol Sci. 1983;62(1-3):219–32.PubMedCrossRef
2.
Hauser SL, et al. Immunohistochemical analysis of the cellular infiltrate in multiple sclerosis lesions. Ann Neurol. 1986;19(6):578–87.PubMedCrossRef
3.
4.
Babbe H, et al. Clonal expansions of CD8(+) T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction. J Exp Med. 2000;192(3):393–404.PubMedPubMedCentralCrossRef
5.
Junker A, et al. Multiple sclerosis: T-cell receptor expression in distinct brain regions. Brain. 2007;130(Pt 11):2789–99.PubMedCrossRef
6.
Skulina C, et al. Multiple sclerosis: brain-infiltrating CD8+ T cells persist as clonal expansions in the cerebrospinal fluid and blood. Proc Natl Acad Sci U S A. 2004;101(8):2428–33.PubMedPubMedCentralCrossRef
7.
Neumann H, Medana IM, Bauer J, Lassmann H. Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases. Trends Neurosci. 2002;25(6):313–9.PubMedCrossRef
8.
Saikali P, et al. NKG2D-mediated cytotoxicity toward oligodendrocytes suggests a mechanism for tissue injury in multiple sclerosis. J Neurosci. 2007;27(5):1220–8.PubMedPubMedCentralCrossRef
9.
10.
Sun D, et al. Myelin antigen-specific CD8+ T cells are encephalitogenic and produce severe disease in C57BL/6 mice. J Immunol. 2001;166(12):7579–87.PubMedCrossRef
11.
Cabarrocas J, Bauer J, Piaggio E, Liblau R, Lassmann H. Effective and selective immune surveillance of the brain by MHC class I-restricted cytotoxic T lymphocytes. Eur J Immunol. 2003;33(5):1174–82.PubMedCrossRef
12.
Zehntner SP, Brisebois M, Tran E, Owens T, Fournier S. Constitutive expression of a costimulatory ligand on antigen-presenting cells in the nervous system drives demyelinating disease. FASEB J. 2003;17(13):1910–2.PubMedCrossRef
13.
Saxena A, et al. Cutting edge: multiple sclerosis-like lesions induced by effector CD8 T cells recognizing a sequestered antigen on oligodendrocytes. J Immunol. 2008;181(3):1617–21.PubMedCrossRef
14.
Ford ML, Evavold BD. Specificity, magnitude, and kinetics of MOG-specific CD8+ T cell responses during experimental autoimmune encephalomyelitis. Eur J Immunol. 2005;35(1):76–85.PubMedCrossRef
15.
Willis CM, et al. Extracellular vesicle fibrinogen induces encephalitogenic CD8+ T cells in a mouse model of multiple sclerosis. Proc Natl Acad Sci U S A. 2019;116(21):10488–93.PubMedPubMedCentralCrossRef
16.
Buckle GJ, Hollsberg P, Hafler DA. Activated CD8+ T cells in secondary progressive MS secrete lymphotoxin. Neurology. 2003;60(4):702–5.PubMedCrossRef
17.
Jewtoukoff V, Lebar R, Bach MA. Oligodendrocyte-specific autoreactive T cells using an alpha/beta T-cell receptor kill their target without self restriction. Proc Natl Acad Sci U S A. 1989;86(8):2824–8.PubMedPubMedCentralCrossRef
18.
Ifergan I, et al. Central nervous system recruitment of effector memory CD8+ T lymphocytes during neuroinflammation is dependent on alpha4 integrin. Brain. 2011;134(Pt 12):3560–77.PubMedCrossRef
19.
Kashi VP, Ortega SB, Karandikar NJ. Neuroantigen-specific autoregulatory CD8+ T cells inhibit autoimmune demyelination through modulation of dendritic cell function. PLoS One. 2014;9(8):e105763.PubMedPubMedCentralCrossRef
20.
Ortega SB, et al. The disease-ameliorating function of autoregulatory CD8 T cells is mediated by targeting of encephalitogenic CD4 T cells in experimental autoimmune encephalomyelitis. J Immunol. 2013;191(1):117–26.PubMedCrossRef
21.
Jiang H, Braunstein NS, Yu B, Winchester R, Chess L. CD8+ T cells control the TH phenotype of MBP-reactive CD4+ T cells in EAE mice. Proc Natl Acad Sci U S A. 2001;98(11):6301–6.PubMedPubMedCentralCrossRef
22.
Jiang H, et al. Regulatory CD8+ T cells fine-tune the myelin basic protein-reactive T cell receptor V beta repertoire during experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2003;100(14):8378–83.PubMedPubMedCentralCrossRef
23.
24.
Chen ML, Yan BS, Kozoriz D, Weiner HL. Novel CD8+ Treg suppress EAE by TGF-beta- and IFN-gamma-dependent mechanisms. Eur J Immunol. 2009;39(12):3423–35.PubMedPubMedCentralCrossRef
25.
Molnarfi N, Benkhoucha M, Funakoshi H, Nakamura T, Lalive PH. Hepatocyte growth factor: a regulator of inflammation and autoimmunity. Autoimmun Rev. 2014.
26.
Benkhoucha M, et al. Hepatocyte growth factor inhibits CNS autoimmunity by inducing tolerogenic dendritic cells and CD25+Foxp3+ regulatory T cells. Proc Natl Acad Sci U S A. 2010;107(14):6424–9.PubMedPubMedCentralCrossRef
27.
28.
Okunishi K, et al. A novel role of hepatocyte growth factor as an immune regulator through suppressing dendritic cell function. J Immunol. 2005;175(7):4745–53.PubMedCrossRef
29.
Futamatsu H, et al. Hepatocyte growth factor ameliorates the progression of experimental autoimmune myocarditis: a potential role for induction of T helper 2 cytokines. Circ Res. 2005;96(8):823–30.PubMedCrossRef
30.
Rutella S, et al. Hepatocyte growth factor favors monocyte differentiation into regulatory interleukin (IL)-10++IL-12low/neg accessory cells with dendritic-cell features. Blood. 2006;108(1):218–27.PubMedCrossRef
31.
Molnarfi N, Benkhoucha M, Juillard C, Bjarnadottir K, Lalive PH. The neurotrophic hepatocyte growth factor induces protolerogenic human dendritic cells. J Neuroimmunol. 2014;267(1-2):105–10.PubMedCrossRef
32.
Yen BL, et al. Multipotent human mesenchymal stromal cells mediate expansion of myeloid-derived suppressor cells via hepatocyte growth factor/c-Met and STAT3. Stem Cell Reports. 2013;1(2):139–51.PubMedPubMedCentralCrossRef
33.
34.
Benkhoucha M, et al. Hepatocyte growth factor limits autoimmune neuroinflammation via glucocorticoid-induced leucine zipper expression in dendritic cells. J Immunol. 2014;193(6):2743–52.PubMedCrossRef
35.
Benkhoucha M, Molnarfi N, Schneiter G, Walker PR, Lalive PH. The neurotrophic hepatocyte growth factor attenuates CD8+ cytotoxic T-lymphocyte activity. J Neuroinflammation. 2013;10:154.PubMedPubMedCentralCrossRef
36.
Komarowska I, et al. Hepatocyte growth factor receptor c-Met instructs T cell cardiotropism and promotes T cell migration to the heart via autocrine chemokine release. Immunity. 2015;42(6):1087–99.PubMedPubMedCentralCrossRef
37.
Bottaro DP, et al. Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product. Science. 1991;251(4995):802–4.PubMedCrossRef
38.
Maina F, Klein R. Hepatocyte growth factor, a versatile signal for developing neurons. Nat Neurosci. 1999;2(3):213–7.PubMedCrossRef
39.
Kitamura K, et al. Hepatocyte growth factor promotes endogenous repair and functional recovery after spinal cord injury. J Neurosci Res. 2007;85(11):2332–42.PubMedCrossRef
40.
Ohya W, Funakoshi H, Kurosawa T, Nakamura T. Hepatocyte growth factor (HGF) promotes oligodendrocyte progenitor cell proliferation and inhibits its differentiation during postnatal development in the rat. Brain Res. 2007;1147:51–65.PubMedCrossRef
41.
Lalive PH, et al. TGF-beta-treated microglia induce oligodendrocyte precursor cell chemotaxis through the HGF-c-Met pathway. Eur J Immunol. 2005;35(3):727–37.PubMedCrossRef
42.
Yan H, Rivkees SA. Hepatocyte growth factor stimulates the proliferation and migration of oligodendrocyte precursor cells. J Neurosci Res. 2002;69(5):597–606.PubMedCrossRef
43.
Di Renzo MF, et al. Selective expression of the Met/HGF receptor in human central nervous system microglia. Oncogene. 1993;8(1):219–22.PubMed
44.
Zamvil SS, Steinman L. The T lymphocyte in experimental allergic encephalomyelitis. Annu Rev Immunol. 1990;8:579–621.PubMedCrossRef
45.
Traugott U, Reinherz EL, Raine CS. Multiple sclerosis. Distribution of T cells, T cell subsets and Ia-positive macrophages in lesions of different ages. J Neuroimmunol. 1983;4(3):201–21.PubMedCrossRef
46.
Neumann H, Schmidt H, Cavalie A, Jenne D, Wekerle H. Major histocompatibility complex (MHC) class I gene expression in single neurons of the central nervous system: differential regulation by interferon (IFN)-gamma and tumor necrosis factor (TNF)-alpha. J Exp Med. 1997;185(2):305–16.PubMedPubMedCentralCrossRef
Metadata
Title
c-Met is expressed by highly autoreactive encephalitogenic CD8+ cells
Authors
Mahdia Benkhoucha
Isis Senoner
Patrice H. Lalive
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2020
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/s12974-019-1676-0

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