CD4c-MetItgα4 T Cell Subset Promotes Murine Neuroinflammation

Overview

Journal J Neuroinflammation

Publisher Biomed Central

Date 2022 Apr 29

PMID 35488271

Authors

Mahdia Benkhoucha

Ngoc Lan Tran

Gautier Breville

Isis Senoner

Paul F Bradfield

Thalia Papayannopoulou

Doron Merkler

Thomas Korn

Patrice H Lalive

Affiliations

Soon will be listed here.

Abstract

Objective: c-Met, a tyrosine kinase receptor, is the unique receptor for hepatocyte growth factor (HGF). The HGF/c-Met axis is reported to modulate cell migration, maturation, cytokine production, and antigen presentation. Here, we report that CD4c-Met T cells are detected at increased levels in experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS).

Methods: c-Met expression by CD4 T cells was analyzed mostly by flow cytometry and by immunohistochemistry from mice and human PBMCs. The in vivo role of CD4c-Met T cells was assessed in EAE.

Results: CD4c-Met T cells found in the CNS during EAE peak disease are characterized by a pro-inflammatory phenotype skewed towards a Th1 and Th17 polarization, with enhanced adhesion and transmigration capacities correlating with increased expression of integrin α4 (Itgα4). The adoptive transfer of Itgα4-expressing CD4Vα3.2c-Met T cells induces increased disease severity compared to CD4Vα3.2c-Met T cells. Finally, CD4c-Met T cells are detected in the brain of MS patients, as well as in the blood with a higher level of Itgα4. These results highlight c-Met as an immune marker of highly pathogenic pro-inflammatory and pro-migratory CD4 T lymphocytes associated with neuroinflammation.

Citing Articles

Understanding immune microenvironment alterations in the brain to improve the diagnosis and treatment of diverse brain diseases.

Xu X, Han Y, Zhang B, Ren Q, Ma J, Liu S Cell Commun Signal. 2024; 22(1):132.

PMID: 38368403 PMC: 10874090. DOI: 10.1186/s12964-024-01509-w.

References

Lalor S, Segal B . Th1-mediated experimental autoimmune encephalomyelitis is CXCR3 independent. Eur J Immunol. 2013; 43(11):2866-74. DOI: 10.1002/eji.201343499. View

Muller M, Carter S, Hofer M, Campbell I . Review: The chemokine receptor CXCR3 and its ligands CXCL9, CXCL10 and CXCL11 in neuroimmunity--a tale of conflict and conundrum. Neuropathol Appl Neurobiol. 2010; 36(5):368-87. DOI: 10.1111/j.1365-2990.2010.01089.x. View

Benkhoucha M, Tran N, Breville G, Senoner I, Jandus C, Lalive P . c-Met enforces proinflammatory and migratory features of human activated CD4 T cells. Cell Mol Immunol. 2021; 18(8):2051-2053. PMC: 8322317. DOI: 10.1038/s41423-021-00721-9. View

Dendrou C, Fugger L, Friese M . Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015; 15(9):545-58. DOI: 10.1038/nri3871. View

Rothhammer V, Heink S, Petermann F, Srivastava R, Claussen M, Hemmer B . Th17 lymphocytes traffic to the central nervous system independently of α4 integrin expression during EAE. J Exp Med. 2011; 208(12):2465-76. PMC: 3256959. DOI: 10.1084/jem.20110434. View

Domingues H, Mues M, Lassmann H, Wekerle H, Krishnamoorthy G . Functional and pathogenic differences of Th1 and Th17 cells in experimental autoimmune encephalomyelitis. PLoS One. 2011; 5(11):e15531. PMC: 3000428. DOI: 10.1371/journal.pone.0015531. View

Sospedra M, Martin R . Immunology of multiple sclerosis. Annu Rev Immunol. 2005; 23:683-747. DOI: 10.1146/annurev.immunol.23.021704.115707. View

Sato W, Tomita A, Ichikawa D, Lin Y, Kishida H, Miyake S . CCR2(+)CCR5(+) T cells produce matrix metalloproteinase-9 and osteopontin in the pathogenesis of multiple sclerosis. J Immunol. 2012; 189(10):5057-65. PMC: 3496198. DOI: 10.4049/jimmunol.1202026. View

Piccio L, Rossi B, Scarpini E, Laudanna C, Giagulli C, Issekutz A . Molecular mechanisms involved in lymphocyte recruitment in inflamed brain microvessels: critical roles for P-selectin glycoprotein ligand-1 and heterotrimeric G(i)-linked receptors. J Immunol. 2002; 168(4):1940-9. DOI: 10.4049/jimmunol.168.4.1940. View

10.

Zhang Y, Han J, Liang X, Zhao L, Zhang F, Rasouli J . miR-23b Suppresses Leukocyte Migration and Pathogenesis of Experimental Autoimmune Encephalomyelitis by Targeting CCL7. Mol Ther. 2017; 26(2):582-592. PMC: 5835026. DOI: 10.1016/j.ymthe.2017.11.013. View

11.

Komarowska I, Coe D, Wang G, Haas R, Mauro C, Kishore M . 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. PMC: 4510150. DOI: 10.1016/j.immuni.2015.05.014. View

12.

Okunishi K, Dohi M, Nakagome K, Tanaka R, Mizuno S, Matsumoto K . A novel role of hepatocyte growth factor as an immune regulator through suppressing dendritic cell function. J Immunol. 2005; 175(7):4745-53. DOI: 10.4049/jimmunol.175.7.4745. View

13.

Codarri L, Gyulveszi G, Tosevski V, Hesske L, Fontana A, Magnenat L . RORγt drives production of the cytokine GM-CSF in helper T cells, which is essential for the effector phase of autoimmune neuroinflammation. Nat Immunol. 2011; 12(6):560-7. DOI: 10.1038/ni.2027. View

14.

Hartmann F, Khademi M, Aram J, Ammann S, Kockum I, Constantinescu C . Multiple sclerosis-associated IL2RA polymorphism controls GM-CSF production in human TH cells. Nat Commun. 2014; 5:5056. DOI: 10.1038/ncomms6056. View

15.

Engelhardt B, Conley F, Kilshaw P, Butcher E . Lymphocytes infiltrating the CNS during inflammation display a distinctive phenotype and bind to VCAM-1 but not to MAdCAM-1. Int Immunol. 1995; 7(3):481-91. DOI: 10.1093/intimm/7.3.481. View

16.

Mars L, Saikali P, Liblau R, Arbour N . Contribution of CD8 T lymphocytes to the immuno-pathogenesis of multiple sclerosis and its animal models. Biochim Biophys Acta. 2010; 1812(2):151-61. PMC: 5052066. DOI: 10.1016/j.bbadis.2010.07.006. View

17.

Glatigny S, Duhen R, Oukka M, Bettelli E . Cutting edge: loss of α4 integrin expression differentially affects the homing of Th1 and Th17 cells. J Immunol. 2011; 187(12):6176-9. PMC: 3237912. DOI: 10.4049/jimmunol.1102515. View

18.

Krishnamoorthy G, Wekerle H . EAE: an immunologist's magic eye. Eur J Immunol. 2009; 39(8):2031-5. DOI: 10.1002/eji.200939568. View

19.

Ransohoff R . Natalizumab for multiple sclerosis. N Engl J Med. 2007; 356(25):2622-9. DOI: 10.1056/NEJMct071462. View

20.

Benkhoucha M, Molnarfi N, Kaya G, Belnoue E, Bjarnadottir K, Dietrich P . Identification of a novel population of highly cytotoxic c-Met-expressing CD8 T lymphocytes. EMBO Rep. 2017; 18(9):1545-1558. PMC: 5579394. DOI: 10.15252/embr.201744075. View