Integrin Alpha L Controls the Homing of Regulatory T Cells During CNS Autoimmunity in the Absence of Integrin Alpha 4

Overview

Journal Sci Rep

Specialty Science

Date 2015 Jan 17

PMID 25592296

Citations 27

Authors

Simon Glatigny

Rebekka Duhen

Carlos Arbelaez

Swarnima Kumari

Estelle Bettelli

Affiliations

Soon will be listed here.

Abstract

Experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), results from an autoimmune attack of the central nervous system (CNS) by effector T helper (Th) 1 and Th17 cells. Regulatory T cells (Treg) can control effector T cells and limit the progression of CNS autoimmunity. Integrin alpha 4 (Itga4) is critical for the entry of Th1 but not Th17 cells into the CNS during EAE. Whether Itga4 controls the homing of Tregs in the CNS and whether Tregs can limit Th17-mediated EAE has, however, not been addressed. Through selective elimination of Itga4 in Foxp3-expressing cells, we show here that Tregs can suppress Th17-mediated EAE and enter into the CNS independently of Itga4. Furthermore, similarly to Th17 cells and in contrast to Th1 cells, Tregs depend on LFA-1 for their entry into the CNS in the absence of Itga4. Therefore, these data suggest that the efficacy of Itga4 neutralization on MS progression may be associated with the prevention of Th1 cells and the maintenance of Tregs migration into the CNS.

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References

Stuve O, Marra C, Bar-Or A, Niino M, Cravens P, Cepok S . Altered CD4+/CD8+ T-cell ratios in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis. Arch Neurol. 2006; 63(10):1383-7. DOI: 10.1001/archneur.63.10.1383. View

Niino M, Bodner C, Simard M, Alatab S, Gano D, Kim H . Natalizumab effects on immune cell responses in multiple sclerosis. Ann Neurol. 2006; 59(5):748-54. DOI: 10.1002/ana.20859. View

Nguyen V, Zeiser R, Dasilva D, Chang D, Beilhack A, Contag C . In vivo dynamics of regulatory T-cell trafficking and survival predict effective strategies to control graft-versus-host disease following allogeneic transplantation. Blood. 2006; 109(6):2649-56. DOI: 10.1182/blood-2006-08-044529. View

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

Stromnes I, Cerretti L, Liggitt D, Harris R, Goverman J . Differential regulation of central nervous system autoimmunity by T(H)1 and T(H)17 cells. Nat Med. 2008; 14(3):337-42. PMC: 2813727. DOI: 10.1038/nm1715. View

Stenner M, Waschbisch A, Buck D, Doerck S, Einsele H, Toyka K . Effects of natalizumab treatment on Foxp3+ T regulatory cells. PLoS One. 2008; 3(10):e3319. PMC: 2553177. DOI: 10.1371/journal.pone.0003319. View

Dugger K, Zinn K, Weaver C, Bullard D, Barnum S . Effector and suppressor roles for LFA-1 during the development of experimental autoimmune encephalomyelitis. J Neuroimmunol. 2008; 206(1-2):22-7. PMC: 2665690. DOI: 10.1016/j.jneuroim.2008.10.006. View

Kleinewietfeld M, Starke M, Di Mitri D, Borsellino G, Battistini L, Rotzschke O . CD49d provides access to "untouched" human Foxp3+ Treg free of contaminating effector cells. Blood. 2008; 113(4):827-36. DOI: 10.1182/blood-2008-04-150524. View

Stephens L, Malpass K, Anderton S . Curing CNS autoimmune disease with myelin-reactive Foxp3+ Treg. Eur J Immunol. 2009; 39(4):1108-17. DOI: 10.1002/eji.200839073. View

10.

Jager A, Dardalhon V, Sobel R, Bettelli E, Kuchroo V . Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with different pathological phenotypes. J Immunol. 2009; 183(11):7169-77. PMC: 2921715. DOI: 10.4049/jimmunol.0901906. View

11.

Chaudhry A, Rudra D, Treuting P, Samstein R, Liang Y, Kas A . CD4+ regulatory T cells control TH17 responses in a Stat3-dependent manner. Science. 2009; 326(5955):986-91. PMC: 4408196. DOI: 10.1126/science.1172702. View

12.

Hu X, Wohler J, Dugger K, Barnum S . beta2-integrins in demyelinating disease: not adhering to the paradigm. J Leukoc Biol. 2009; 87(3):397-403. PMC: 3212424. DOI: 10.1189/jlb.1009654. View

13.

Axtell R, de Jong B, Boniface K, van der Voort L, Bhat R, De Sarno P . T helper type 1 and 17 cells determine efficacy of interferon-beta in multiple sclerosis and experimental encephalomyelitis. Nat Med. 2010; 16(4):406-12. PMC: 3042885. DOI: 10.1038/nm.2110. View

14.

Fletcher J, Lalor S, Sweeney C, Tubridy N, Mills K . T cells in multiple sclerosis and experimental autoimmune encephalomyelitis. Clin Exp Immunol. 2010; 162(1):1-11. PMC: 2990924. DOI: 10.1111/j.1365-2249.2010.04143.x. View

15.

Gultner S, Kuhlmann T, Hesse A, Weber J, Riemer C, Baier M . Reduced Treg frequency in LFA-1-deficient mice allows enhanced T effector differentiation and pathology in EAE. Eur J Immunol. 2010; 40(12):3403-12. DOI: 10.1002/eji.201040576. View

16.

Anderton S . Treg and T-effector cells in autoimmune CNS inflammation: a delicate balance, easily disturbed. Eur J Immunol. 2010; 40(12):3321-4. DOI: 10.1002/eji.201041100. View

17.

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

18.

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

19.

Ding Y, Xu J, Bromberg J . Regulatory T cell migration during an immune response. Trends Immunol. 2012; 33(4):174-80. PMC: 3319498. DOI: 10.1016/j.it.2012.01.002. View

20.

Bloomgren G, Richman S, Hotermans C, Subramanyam M, Goelz S, Natarajan A . Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med. 2012; 366(20):1870-80. DOI: 10.1056/NEJMoa1107829. View