Differential Regulation of Central Nervous System Autoimmunity by T(H)1 and T(H)17 Cells

Overview

Journal Nat Med

Specialties General Medicine
Molecular Biology

Date 2008 Feb 19

PMID 18278054

Citations 291

Authors

Ingunn M Stromnes

Lauren M Cerretti

Denny Liggitt

Robert A Harris

Joan M Goverman

Affiliations

Soon will be listed here.

Abstract

Multiple sclerosis is an inflammatory, demyelinating disease of the central nervous system (CNS) characterized by a wide range of clinical signs. The location of lesions in the CNS is variable and is a crucial determinant of clinical outcome. Multiple sclerosis is believed to be mediated by myelin-specific T cells, but the mechanisms that determine where T cells initiate inflammation are unknown. Differences in lesion distribution have been linked to the HLA complex, suggesting that T cell specificity influences sites of inflammation. We demonstrate that T cells that are specific for different myelin epitopes generate populations characterized by different T helper type 17 (T(H)17) to T helper type 1 (T(H)1) ratios depending on the functional avidity of interactions between TCR and peptide-MHC complexes. Notably, the T(H)17:T(H)1 ratio of infiltrating T cells determines where inflammation occurs in the CNS. Myelin-specific T cells infiltrate the meninges throughout the CNS, regardless of the T(H)17:T(H)1 ratio. However, T cell infiltration and inflammation in the brain parenchyma occurs only when T(H)17 cells outnumber T(H)1 cells and trigger a disproportionate increase in interleukin-17 expression in the brain. In contrast, T cells showing a wide range of T(H)17:T(H)1 ratios induce spinal cord parenchymal inflammation. These findings reveal critical differences in the regulation of inflammation in the brain and spinal cord.

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References

Abromson-Leeman S, Bronson R, Luo Y, Berman M, Leeman R, Leeman J . T-cell properties determine disease site, clinical presentation, and cellular pathology of experimental autoimmune encephalomyelitis. Am J Pathol. 2004; 165(5):1519-33. PMC: 1618652. DOI: 10.1016/S0002-9440(10)63410-4. View

Park H, Li Z, Yang X, Chang S, Nurieva R, Wang Y . A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat Immunol. 2005; 6(11):1133-41. PMC: 1618871. DOI: 10.1038/ni1261. View

Berahovich R, Miao Z, Wang Y, Premack B, Howard M, Schall T . Proteolytic activation of alternative CCR1 ligands in inflammation. J Immunol. 2005; 174(11):7341-51. DOI: 10.4049/jimmunol.174.11.7341. View

Mendel I, Kerlero de Rosbo N, Ben-Nun A . A myelin oligodendrocyte glycoprotein peptide induces typical chronic experimental autoimmune encephalomyelitis in H-2b mice: fine specificity and T cell receptor V beta expression of encephalitogenic T cells. Eur J Immunol. 1995; 25(7):1951-9. DOI: 10.1002/eji.1830250723. View

Fitzgerald D, Ciric B, Touil T, Harle H, Grammatikopolou J, Das Sarma J . Suppressive effect of IL-27 on encephalitogenic Th17 cells and the effector phase of experimental autoimmune encephalomyelitis. J Immunol. 2007; 179(5):3268-75. DOI: 10.4049/jimmunol.179.5.3268. View

Stromnes I, Goverman J . Active induction of experimental allergic encephalomyelitis. Nat Protoc. 2007; 1(4):1810-9. DOI: 10.1038/nprot.2006.285. View

Kjellen P, Jansson L, Vestberg M, Andersson A, Mattsson R, Holmdahl R . The H2-Ab gene influences the severity of experimental allergic encephalomyelitis induced by proteolipoprotein peptide 103-116. J Neuroimmunol. 2001; 120(1-2):25-33. DOI: 10.1016/s0165-5728(01)00407-6. View

Storch M, Stefferl A, Brehm U, Weissert R, Wallstrom E, Kerschensteiner M . Autoimmunity to myelin oligodendrocyte glycoprotein in rats mimics the spectrum of multiple sclerosis pathology. Brain Pathol. 1998; 8(4):681-94. PMC: 8098227. DOI: 10.1111/j.1750-3639.1998.tb00194.x. View

Tester A, Cox J, Connor A, Starr A, Dean R, Puente X . LPS responsiveness and neutrophil chemotaxis in vivo require PMN MMP-8 activity. PLoS One. 2007; 2(3):e312. PMC: 1819564. DOI: 10.1371/journal.pone.0000312. View

10.

van der Veen R . Nitric oxide and T helper cell immunity. Int Immunopharmacol. 2001; 1(8):1491-500. DOI: 10.1016/s1567-5769(01)00093-5. View

11.

Toft-Hansen H, Nuttall R, Edwards D, Owens T . Key metalloproteinases are expressed by specific cell types in experimental autoimmune encephalomyelitis. J Immunol. 2004; 173(8):5209-18. DOI: 10.4049/jimmunol.173.8.5209. View

12.

Tsunoda I, Kuang L, Theil D, Fujinami R . Antibody association with a novel model for primary progressive multiple sclerosis: induction of relapsing-remitting and progressive forms of EAE in H2s mouse strains. Brain Pathol. 2000; 10(3):402-18. PMC: 8098387. DOI: 10.1111/j.1750-3639.2000.tb00272.x. View

13.

Badie B, Schartner J, Vorpahl J, Preston K . Interferon-gamma induces apoptosis and augments the expression of Fas and Fas ligand by microglia in vitro. Exp Neurol. 2000; 162(2):290-6. DOI: 10.1006/exnr.1999.7345. View

14.

Muller D, Pender M, Greer J . A neuropathological analysis of experimental autoimmune encephalomyelitis with predominant brain stem and cerebellar involvement and differences between active and passive induction. Acta Neuropathol. 2000; 100(2):174-82. DOI: 10.1007/s004019900163. View

15.

Cheng X, Zhao Z, Ventura E, Gran B, Shindler K, Rostami A . The PD-1/PD-L pathway is up-regulated during IL-12-induced suppression of EAE mediated by IFN-gamma. J Neuroimmunol. 2007; 185(1-2):75-86. PMC: 2716290. DOI: 10.1016/j.jneuroim.2007.01.012. View

16.

Harrington L, Hatton R, Mangan P, Turner H, Murphy T, Murphy K . Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat Immunol. 2005; 6(11):1123-32. DOI: 10.1038/ni1254. View

17.

Cruz A, Khader S, Torrado E, Fraga A, Pearl J, Pedrosa J . Cutting edge: IFN-gamma regulates the induction and expansion of IL-17-producing CD4 T cells during mycobacterial infection. J Immunol. 2006; 177(3):1416-20. DOI: 10.4049/jimmunol.177.3.1416. View

18.

Wensky A, Furtado G, Marcondes M, Chen S, Manfra D, Lira S . IFN-gamma determines distinct clinical outcomes in autoimmune encephalomyelitis. J Immunol. 2005; 174(3):1416-23. DOI: 10.4049/jimmunol.174.3.1416. View

19.

Agrawal S, Anderson P, Durbeej M, van Rooijen N, Ivars F, Opdenakker G . Dystroglycan is selectively cleaved at the parenchymal basement membrane at sites of leukocyte extravasation in experimental autoimmune encephalomyelitis. J Exp Med. 2006; 203(4):1007-19. PMC: 2118280. DOI: 10.1084/jem.20051342. View

20.

Brabb T, Von Dassow P, Ordonez N, Schnabel B, Duke B, Goverman J . In situ tolerance within the central nervous system as a mechanism for preventing autoimmunity. J Exp Med. 2000; 192(6):871-80. PMC: 2193284. DOI: 10.1084/jem.192.6.871. View