Neuroprotective intervention by interferon-γ blockade prevents CD8+ T cell-mediated dendrite and synapse loss

Journal of Experimental Medicine

Volumn 210, Issue 10, 2013, Pages 2087-2103

  Kreutzfeldt, Mario ^a,b   Bergthaler, Andreas ^a,c   Fernandez, Marylise ^a   Brück, Wolfgang ^d   Steinbach, Karin ^a,b   Vorm, Mariann ^d   Coras, Roland ^e   Blümcke, Ingmar ^e   Bonilla, Weldy V ^a   Fleige, Anne ^f   Forman, Ruth ^g   Müller, Werner ^g   Becher, Burkhard ^h   Misgeld, Thomas ^i,j,l   Kerschensteiner, Martin ^k,l   Pinschewer, Daniel D ^a   Merkler, Doron ^a,b,d  

^a UNIVERSITY OF GENEVA   (Switzerland)

^b GENEVA UNIVERSITY HOSPITALS   (Switzerland)

^c ERICH SCHMID INSTITUTE OF MATERIALS SCIENCE   (Austria)

^d UNIVERSITY OF GÖTTINGEN   (Germany)

^e UNIVERSITY HOSPITAL ERLANGEN   (Germany)

^f TECHNICAL UNIVERSITY OF BRAUNSCHWEIG   (Germany)

^g UNIVERSITY OF MANCHESTER   (United Kingdom)

^h UNIVERSITY OF ZURICH   (Switzerland)

ⁱ TECHNICAL UNIVERSITY OF MUNICH   (Germany)

^j GERMAN CENTER FOR NEURODEGENERATIVE DISEASES DZNE   (Germany)

^k UNIVERSITY OF MUNICH   (Germany)

^l Technische Universität München Munich Cluster for Systems Neurology   (Germany)

more..

Author keywords

[No Author keywords available]

Indexed keywords

EID: 84885463512     PISSN: 00221007     EISSN: 15409538     Source Type: Journal    
DOI: 10.1084/jem.20122143     Document Type: Article

References (85)

1. Abrams, J.S., M.G. Roncarolo, H. Yssel, U. Andersson, G.J. Gleich, and J.E. Silver. 1992. Strategies of anti-cytokine monoclonal antibody development: immunoassay of IL-10 and IL-5 in clinical samples. Immunol. Rev. 127:5-24. http://dx.doi.org/10.1111/j.1600-065X.1992.tb01406.x
2. Adachi, M., S. Suematsu, T. Kondo, J. Ogasawara, T. Tanaka, N. Yoshida, and S. Nagata. 1995. Targeted mutation in the Fas gene causes hyperplasia in peripheral lymphoid organs and liver. Nat. Genet. 11:294-300. http:// dx.doi.org/10.1038/ng1195-294
3. Albert, M.L., and R.B. Darnell. 2004. Paraneoplastic neurological degenerations: keys to tumour immunity. Nat. Rev. Cancer. 4:36-44. http://dx.doi.org/10.1038/nrc1255
4. Battegay, M., S. Cooper, A. Althage, J. Bänziger, H. Hengartner, and R.M. Zinkernagel. 1991. Quantification of lymphocytic choriomeningitis virus with an immunological focus assay in 24- or 96-well plates. J. Virol. Methods. 33:191-198. http://dx.doi.org/10.1016/0166-0934(91)90018-U
5. Bergthaler, A., D. Merkler, E. Horvath, L. Bestmann, and D.D. Pinschewer. 2007. Contributions of the lymphocytic choriomeningitis virus glycoprotein and polymerase to strain-specific differences in murine liver pathogenicity. J. Gen. Virol. 88:592-603. http://dx.doi.org/10.1099/vir.0.82428-0
6. Bien, C.G., H. Urbach, M. Deckert, J. Schramm, O.D. Wiestler, H. Lassmann, and C.E. Elger. 2002. Diagnosis and staging of Rasmussen's encephalitis by serial MRI and histopathology. Neurology. 58:250-257. http://dx.doi.org/10.1212/WNL.58.2.250
7. Bien, C.G., T. Granata, C. Antozzi, J.H. Cross, O. Dulac, M. Kurthen, H. Lassmann, R. Mantegazza, J.G. Villemure, R. Spreafico, and C.E. Elger. 2005. Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement. Brain. 128:454-471. http://dx.doi .org/10.1093/brain/awh415
8. Binder, G.K., and D.E. Griffin. 2001. Interferon-gamma-mediated sitespecific clearance of alphavirus from CNS neurons. Science. 293:303-306. http://dx.doi.org/10.1126/science.1059742
9. Brown, S.M., J.H. Subak-Sharpe, K.G. Warren, Z. Wroblewska, and H. Koprowski. 1979. Detection by complementation of defective or uninducible (herpes simplex type 1) virus genomes latent in human ganglia. Proc. Natl. Acad. Sci. USA. 76:2364-2368. http://dx.doi.org/10.1073/pnas.76.5.2364
10. Burdeinick-Kerr, R., and D.E. Griffin. 2005. Gamma interferon-dependent, noncytolytic clearance of sindbis virus infection from neurons in vitro. J. Virol. 79:5374-5385. http://dx.doi.org/10.1128/JVI.79.9.5374-5385.2005
11. Campbell, G.R., I. Ziabreva, A.K. Reeve, K.J. Krishnan, R. Reynolds, O. Howell, H. Lassmann, D.M. Turnbull, and D.J. Mahad. 2011. Mitochondrial DNA deletions and neurodegeneration in multiple sclerosis. Ann. Neurol. 69:481-492. http://dx.doi.org/10.1002/ana.22109
12. Chevalier, G., E. Suberbielle, C. Monnet, V. Duplan, G. Martin-Blondel, F. Farrugia, G. Le Masson, R. Liblau, and D. Gonzalez-Dunia. 2011. Neurons are MHC class I-dependent targets for CD8 T cells upon neurotropic viral infection. PLoS Pathog. 7:e1002393. http://dx.doi.org/10.1371/journal.ppat.1002393
13. Cole, G.A., N. Nathanson, and R.A. Prendergast. 1972. Requirement for theta-bearing cells in lymphocytic choriomeningitis virus-induced central nervous system disease. Nature. 238:335-337. http://dx.doi.org/10.1038/238335a0
14. Dalmau, J., and M.R. Rosenfeld. 2008. Paraneoplastic syndromes of the CNS. Lancet Neurol. 7:327-340. http://dx.doi.org/10.1016/S1474-4422(08)70060-7
15. Deb, C., R.G. Lafrance-Corey, L. Zoecklein, L. Papke, M. Rodriguez, and C.L. Howe. 2009. Demyelinated axons and motor function are protected by genetic deletion of perforin in a mouse model of multiple sclerosis. J. Neuropathol. Exp. Neurol. 68:1037-1048. http://dx.doi.org/10.1097/NEN.0b013e3181b5417e
16. Deb, C., R.G. Lafrance-Corey, W.F. Schmalstieg, B.M. Sauer, H. Wang, C.L. German, A.J. Windebank, M. Rodriguez, and C.L. Howe. 2010. CD8+ T cells cause disability and axon loss in a mouse model of multiple sclerosis. PLoS ONE. 5:e12478. http://dx.doi.org/10.1371/journal.pone.0012478
17. Dewachter, I., D. Reversé, N. Caluwaerts, L. Ris, C. Kuipéri, C. Van den Haute, K. Spittaels, L. Umans, L. Serneels, E. Thiry, et al. 2002. Neuronal deficiency of presenilin 1 inhibits amyloid plaque formation and corrects hippocampal long-term potentiation but not a cognitive defect of amyloid precursor protein [V717I] transgenic mice. J. Neurosci. 22: 3445-3453.
18. Dutta, R., J. McDonough, X. Yin, J. Peterson, A. Chang, T. Torres, T. Gudz, W.B. Macklin, D.A. Lewis, R.J. Fox, et al. 2006. Mitochondrial dysfunction as a cause of axonal degeneration in multiple sclerosis patients. Ann. Neurol. 59:478-489. http://dx.doi.org/10.1002/ana.20736
19. Emonet, S.F., L. Garidou, D.B. McGavern, and J.C. de la Torre. 2009. Generation of recombinant lymphocytic choriomeningitis viruses with trisegmented genomes stably expressing two additional genes of interest. Proc. Natl. Acad. Sci. USA. 106:3473-3478. http://dx.doi.org/10.1073/pnas.0900088106
20. Farrell, M.A., L. Cheng, M.E. Cornford, W.W. Grody, and H.V. Vinters. 1991. Cytomegalovirus and Rasmussen's encephalitis. Lancet. 337:1551-1552. http://dx.doi.org/10.1016/0140-6736(91)93249-9
21. Feng, G., R.H. Mellor, M. Bernstein, C. Keller-Peck, Q.T. Nguyen, M. Wallace, J.M. Nerbonne, J.W. Lichtman, and J.R. Sanes. 2000. Imaging neuronal subsets in transgenic mice expressing multiple spectral variants of GFP. Neuron. 28:41-51. http://dx.doi.org/10.1016/S0896-6273(00)00084-2
22. Friedman, H., L. Ch'ien, and D. Parham. 1977. Virus in brain of child with hemiplegia, hemiconvulsions, and epilepsy. Lancet. 2:666. http://dx.doi.org/10.1016/S0140-6736(77)92540-5
23. Friese, M.A., and L. Fugger. 2005. Autoreactive CD8+ T cells in multiple sclerosis: a new target for therapyγ Brain. 128:1747-1763. http://dx.doi.org/10.1093/brain/awh578
24. Garin, N., and G. Escher. 2001. The development of inhibitory synaptic specializations in the mouse deep cerebellar nuclei. Neuroscience. 105:431- 441. http://dx.doi.org/10.1016/S0306-4522(01)00127-0
25. Gilmore, C.P., I. Donaldson, L. Bö, T. Owens, J. Lowe, and N. Evangelou. 2009. Regional variations in the extent and pattern of grey matter demyelination in multiple sclerosis: a comparison between the cerebral cortex, cerebellar cortex, deep grey matter nuclei and the spinal cord. J. Neurol. Neurosurg. Psychiatry. 80:182-187. http://dx.doi.org/10.1136/jnnp.2008.148767
26. Goverman, J. 2009. Autoimmune T cell responses in the central nervous system. Nat. Rev. Immunol. 9:393-407. http://dx.doi.org/10.1038/nri2550
27. Guidotti, L.G., T. Ishikawa, M.V. Hobbs, B. Matzke, R. Schreiber, and F.V. Chisari. 1996. Intracellular inactivation of the hepatitis B virus by cytotoxic T lymphocytes. Immunity. 4:25-36. http://dx.doi.org/10.1016/S1074-7613(00)80295-2
28. Hauser, S.L., A.K. Bhan, F. Gilles, M. Kemp, C. Kerr, and H.L. Weiner. 1986. Immunohistochemical analysis of the cellular infiltrate in multiple sclerosis lesions. Ann. Neurol. 19:578-587. http://dx.doi.org/10.1002/ana.410190610
29. Hommes, D.W., T.L. Mikhajlova, S. Stoinov, D. Stimac, B. Vucelic, J. Lonovics, M. Zákuciová, G. D'Haens, G. Van Assche, S. Ba, et al. 2006. Fontolizumab, a humanised anti-interferon gamma antibody, demonstrates safety and clinical activity in patients with moderate to severe Crohn's disease. Gut. 55:1131-1137. http://dx.doi.org/10.1136/gut.2005.079392
30. Huang, S., W. Hendriks, A. Althage, S. Hemmi, H. Bluethmann, R. Kamijo, J. Vilcek, R.M. Zinkernagel, and M. Aguet. 1993. Immune response in mice that lack the interferon-gamma receptor. Science. 259:1742-1745. http://dx.doi.org/10.1126/science.8456301
31. Johnson, G.V., and R.S. Jope. 1992. The role of microtubule-associated protein 2 (MAP-2)in neuronal growth, plasticity, and degeneration. J. Neurosci. Res. 33:505-512. http://dx.doi.org/10.1002/jnr.490330402
32. Joly, E., and M.B. Oldstone. 1992. Neuronal cells are deficient in loading peptides onto MHC class I molecules. Neuron. 8:1185-1190. http://dx.doi.org/10.1016/0896-6273(92)90138-4
33. Joly, E., L. Mucke, and M.B. Oldstone. 1991. Viral persistence in neurons explained by lack of major histocompatibility class I expression. Science. 253:1283-1285. http://dx.doi.org/10.1126/science.1891717
34. Kägi, D., B. Ledermann, K. Bürki, P. Seiler, B. Odermatt, K.J. Olsen, E.R. Podack, R.M. Zinkernagel, and H. Hengartner. 1994. Cytotoxicity mediated by T cells and natural killer cells is greatly impaired in perforin- deficient mice. Nature. 369:31-37. http://dx.doi.org/10.1038/369031a0
35. Kägi, D., B. Odermatt, P.S. Ohashi, R.M. Zinkernagel, and H. Hengartner. 1996. Development of insulitis without diabetes in transgenic mice lacking perforin-dependent cytotoxicity. J. Exp. Med. 183:2143-2152. http://dx.doi.org/10.1084/jem.183.5.2143
36. Kallmann, B.A., V. Hummel, T. Lindenlaub, K. Ruprecht, K.V. Toyka, and P. Rieckmann. 2000. Cytokine-induced modulation of cellular adhesion to human cerebral endothelial cells is mediated by soluble vascular cell adhesion molecule-1. Brain. 123:687-697. http://dx.doi.org/10.1093/brain/123.4.687
37. Khanna, K.M., R.H. Bonneau, P.R. Kinchington, and R.L. Hendricks. 2003. Herpes simplex virus-specific memory CD8+ T cells are selectively activated and retained in latently infected sensory ganglia. Immunity. 18:593-603. http://dx.doi.org/10.1016/S1074-7613(03)00112-2
38. Kim, E.Y., J.J. Priatel, S.J. Teh, and H.S. Teh. 2006. TNF receptor type 2 (p75)functions as a costimulator for antigen-driven T cell responses in vivo. J. Immunol. 176:1026-1035.
39. Kim, I.J., H.N. Beck, P.J. Lein, and D. Higgins. 2002. Interferon gamma induces retrograde dendritic retraction and inhibits synapse formation. J. Neurosci. 22:4530-4539.
40. Li, Y., A. Uccelli, K.D. Laxer, M.C. Jeong, H.V. Vinters, W.W. Tourtellotte, S.L. Hauser, and J.R. Oksenberg. 1997. Local-clonal expansion of infiltrating T lymphocytes in chronic encephalitis of Rasmussen. J. Immunol. 158:1428-1437.
41. Lin, W., A. Kemper, J.L. Dupree, H.P. Harding, D. Ron, and B. Popko. 2006. Interferon-gamma inhibits central nervous system remyelination through a process modulated by endoplasmic reticulum stress. Brain. 129:1306-1318. http://dx.doi.org/10.1093/brain/awl044
42. Liu, Y., I. Teige, B. Birnir, and S. Issazadeh-Navikas. 2006. Neuron-mediated generation of regulatory T cells from encephalitogenic T cells suppresses EAE. Nat. Med. 12:518-525. http://dx.doi.org/10.1038/nm1402
43. Luche, H., O. Weber, T. Nageswara Rao, C. Blum, and H.J. Fehling. 2007. Faithful activation of an extra-bright red fluorescent protein in "knockin" Cre-reporter mice ideally suited for lineage tracing studies. Eur. J. Immunol. 37:43-53. http://dx.doi.org/10.1002/eji.200636745
44. Mahad, D.J., I. Ziabreva, G. Campbell, N. Lax, K. White, P.S. Hanson, H. Lassmann, and D.M. Turnbull. 2009. Mitochondrial changes within axons in multiple sclerosis. Brain. 132:1161-1174. http://dx.doi.org/10.1093/brain/awp046
45. Manning, P.T., E.M. Johnson Jr., C.L. Wilcox, M.A. Palmatier, and J.H. Russell. 1987. MHC-specific cytotoxic T lymphocyte killing of dissociated sympathetic neuronal cultures. Am. J. Pathol. 128:395-409.
46. Manrique-Hoyos, N., T. Jürgens, M. Grønborg, M. Kreutzfeldt, M. Schedensack, T. Kuhlmann, C. Schrick, W. Brück, H. Urlaub, M. Simons, and D. Merkler. 2012. Late motor decline after accomplished remyelination: impact for progressive multiple sclerosis. Ann. Neurol. 71:227-244. http://dx.doi.org/10.1002/ana.22681
47. McDole, J.R., S.C. Danzer, R.Y. Pun, Y. Chen, H.L. Johnson, I. Pirko, and A.J. Johnson. 2010. Rapid formation of extended processes and engagement of Theiler's virus-infected neurons by CNS-infiltrating CD8 T cells. Am. J. Pathol. 177:1823-1833. http://dx.doi.org/10.2353/ajpath.2010.100231
48. Medana, I.M., A. Gallimore, A. Oxenius, M.M. Martinic, H. Wekerle, and H. Neumann. 2000. MHC class I-restricted killing of neurons by virus-specific CD8+ T lymphocytes is effected through the Fas/FasL, but not the perforin pathway. Eur. J. Immunol. 30:3623-3633. http://dx.doi.org/10.1002/1521-4141(200012)30:12<3623::AID-IMMU3623>3 .0.CO;2-F
49. Medana, I., Z. Li, A. Flügel, J. Tschopp, H. Wekerle, and H. Neumann. 2001a. Fas ligand (CD95L)protects neurons against perforin-mediated T lymphocyte cytotoxicity. J. Immunol. 167:674-681.
50. Medana, I., M.A. Martinic, H. Wekerle, and H. Neumann. 2001b. Transection of major histocompatibility complex class I-induced neurites by cytotoxic T lymphocytes. Am. J. Pathol. 159:809-815. http://dx.doi.org/10.1016/S0002-9440(10)61755-5
51. Merkler, D., E. Horvath, W. Bruck, R.M. Zinkernagel, J.C. Del la Torre, and D.D. Pinschewer. 2006. "Viral déjá vu" elicits organ-specific immune disease independent of reactivity to self. J. Clin. Invest. 116:1254-1263. http://dx.doi.org/10.1172/JCI27372
52. Meuth, S.G., A.M. Herrmann, O.J. Simon, V. Siffrin, N. Melzer, S. Bittner, P. Meuth, H.F. Langer, S. Hallermann, N. Boldakowa, et al. 2009. Cytotoxic CD8+ T cell-neuron interactions: perforin-dependent electrical silencing precedes but is not causally linked to neuronal cell death. J. Neurosci. 29:15397-15409. http://dx.doi.org/10.1523/JNEUROSCI.4339-09.2009
53. Mizuno, T., G. Zhang, H. Takeuchi, J. Kawanokuchi, J. Wang, Y. Sonobe, S. Jin, N. Takada, Y. Komatsu, and A. Suzumura. 2008. Interferon-gamma directly induces neurotoxicity through a neuron specific, calciumpermeable complex of IFN-gamma receptor and AMPA GluR1 receptor. FASEB J. 22:1797-1806. http://dx.doi.org/10.1096/fj.07-099499
54. Murray, P.D., D.B. McGavern, X. Lin, M.K. Njenga, J. Leibowitz, L.R. Pease, and M. Rodriguez. 1998. Perforin-dependent neurologic injury in a viral model of multiple sclerosis. J. Neurosci. 18:7306-7314.
55. Neumann, H., A. Cavalié, D.E. Jenne, and H. Wekerle. 1995. Induction of MHC class I genes in neurons. Science. 269:549-552. http://dx.doi.org/10.1126/science.7624779
56. Neumann, H., H. Schmidt, A. Cavalié, D. Jenne, and H. Wekerle. 1997. Major histocompatibility complex (MHC)class I gene expression in single neurons of the central nervous system: differential regulation by interferon (IFN)-γ and tumor necrosis factor (TNF)-γ. J. Exp. Med. 185:305-316. http://dx.doi.org/10.1084/jem.185.2.305
57. Neumann, H., I.M. Medana, J. Bauer, and H. Lassmann. 2002. Cytotoxic T lymphocytes in autoimmune and degenerative CNS diseases. Trends Neurosci. 25:313-319. http://dx.doi.org/10.1016/S0166-2236(02)02154-9
58. Nikic, I., D. Merkler, C. Sorbara, M. Brinkoetter, M. Kreutzfeldt, F.M. Bareyre, W. Brück, D. Bishop, T. Misgeld, and M. Kerschensteiner. 2011. A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis. Nat. Med. 17:495-499. http://dx.doi.org/10.1038/nm.2324
59. Olert, J., K.H. Wiedorn, T. Goldmann, H. Kühl, Y. Mehraein, H. Scherthan, F. Niketeghad, E. Vollmer, A.M. Müller, and J. Müller-Navia. 2001. HOPE fixation: a novel fixing method and paraffin-embedding technique for human soft tissues. Pathol. Res. Pract. 197:823-826. http://dx.doi.org/10.1078/0344-0338-00166
60. Owens, G.C., M.N. Huynh, J.W. Chang, D.L. McArthur, M.J. Hickey, H.V. Vinters, G.W. Mathern, and C.A. Kruse. 2013. Differential expression of interferon-γ and chemokine genes distinguishes Rasmussen encephalitis from cortical dysplasia and provides evidence for an early Th1 immune response. J. Neuroinflammation. 10:56. http://dx.doi.org/10.1186/1742-2094-10-56
61. Panitch, H.S., R.L. Hirsch, J. Schindler, and K.P. Johnson. 1987. Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology. 37:1097-1102. http://dx.doi.org/10.1212/WNL.37.7.1097
62. Pardo, C.A., E.P. Vining, L. Guo, R.L. Skolasky, B.S. Carson, and J.M. Freeman. 2004. The pathology of Rasmussen syndrome: stages of cortical involvement and neuropathological studies in 45 hemispherectomies. Epilepsia. 45:516-526. http://dx.doi.org/10.1111/j.0013-9580.2004.33103.x
63. Peschon, J.J., D.S. Torrance, K.L. Stocking, M.B. Glaccum, C. Otten, C.R. Willis, K. Charrier, P.J. Morrissey, C.B. Ware, and K.M. Mohler. 1998. TNF receptor-deficient mice reveal divergent roles for p55 and p75 in several models of inflammation. J. Immunol. 160:943-952.
64. Pinschewer, D.D., L. Flatz, R. Steinborn, E. Horvath, M. Fernandez, H. Lutz, M. Suter, and A. Bergthaler. 2010a. Innate and adaptive immune control of genetically engineered live-attenuated arenavirus vaccine prototypes. Int. Immunol. 22:749-756. http://dx.doi.org/10.1093/intimm/dxq061
65. Pinschewer, D.D., M. Schedensack, A. Bergthaler, E. Horvath, W. Brück, M. Löhning, and D. Merkler. 2010b. T cells can mediate viral clearance from ependyma but not from brain parenchyma in a major histocompatibility class I- and perforin-independent manner. Brain. 133:1054-1066. http://dx.doi.org/10.1093/brain/awq028
66. Pircher, H., K. Bürki, R. Lang, H. Hengartner, and R.M. Zinkernagel. 1989. Tolerance induction in double specific T-cell receptor transgenic mice varies with antigen. Nature. 342:559-561. http://dx.doi.org/10.1038/342559a0
67. Platanias, L.C. 2005. Mechanisms of type-I- and type-II-interferonmediated signalling. Nat. Rev. Immunol. 5:375-386. http://dx.doi.org/10.1038/nri1604
68. Probst, H.C., K. Tschannen, A. Gallimore, M. Martinic, M. Basler, T. Dumrese, E. Jones, and M.F. van den Broek. 2003. Immunodominance of an antiviral cytotoxic T cell response is shaped by the kinetics of viral protein expression. J. Immunol. 171:5415-5422.
69. Rall, G.F., L. Mucke, and M.B. Oldstone. 1995. Consequences of cytotoxic T lymphocyte interaction with major histocompatibility complex class I-expressing neurons in vivo. J. Exp. Med. 182:1201-1212. http://dx.doi.org/10.1084/jem.182.5.1201
70. Ramana, C.V., M.P. Gil, R.D. Schreiber, and G.R. Stark. 2002. Stat1- dependent and -independent pathways in IFN-gamma-dependent signaling. Trends Immunol. 23:96-101. http://dx.doi.org/10.1016/S1471- 4906(01)02118-4
71. Rasmussen, T., J. Olszewski, and D. Lloydsmith. 1958. Focal seizures due to chronic localized encephalitis. Neurology. 8:435-445. http://dx.doi.org/10.1212/WNL.8.6.435
72. Reinisch, W., W. de Villiers, L. Bene, L. Simon, I. Rácz, S. Katz, I. Altorjay, B. Feagan, D. Riff, C.N. Bernstein, et al. 2010. Fontolizumab in moderate to severe Crohn's disease: a phase 2, randomized, double-blind, placebo-controlled, multiple-dose study. Inflamm. Bowel Dis. 16:233- 242. http://dx.doi.org/10.1002/ibd.21038
73. Rensing-Ehl, A., U. Malipiero, M. Irmler, J. Tschopp, D. Constam, and A. Fontana. 1996. Neurons induced to express major histocompatibility complex class I antigen are killed via the perforin and not the Fas (APO-1/CD95)pathway. Eur. J. Immunol. 26:2271-2274. http://dx.doi.org/10.1002/eji.1830260945
74. Scheikl, T., B. Pignolet, C. Dalard, S. Desbois, D. Raison, M. Yamazaki, A. Saoudi, J. Bauer, H. Lassmann, H. Hardin-Pouzet, and R.S. Liblau. 2012. Cutting edge: neuronal recognition by CD8 T cells elicits central diabetes insipidus. J. Immunol. 188:4731-4735. http://dx.doi.org/10.4049/jimmunol.1102998
75. Schwab, N., C.G. Bien, A. Waschbisch, A. Becker, G.H. Vince, K. Dornmair, and H. Wiendl. 2009. CD8+ T-cell clones dominate brain infiltrates in Rasmussen encephalitis and persist in the periphery. Brain. 132:1236-1246. http://dx.doi.org/10.1093/brain/awp003
76. Sequiera, L.W., L.C. Jennings, L.H. Carrasco, M.A. Lord, A. Curry, and R.N. Sutton. 1979. Detection of herpes-simplex viral genome in brain tissue. Lancet. 2:609-612. http://dx.doi.org/10.1016/S0140-6736(79)91667-2
77. Shinkai, Y., G. Rathbun, K.P. Lam, E.M. Oltz, V. Stewart, M. Mendelsohn, J. Charron, M. Datta, F. Young, A.M. Stall, et al. 1992. RAG-2- deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. 68:855-867. http://dx.doi.org/10.1016/0092-8674(92)90029-C
78. Shrestha, B., and M.S. Diamond. 2007. Fas ligand interactions contribute to CD8+ T-cell-mediated control of West Nile virus infection in the central nervous system. J. Virol. 81:11749-11757. http://dx.doi.org/10.1128/JVI.01136-07
79. Sobottka, B., M.D. Harrer, U. Ziegler, K. Fischer, H. Wiendl, T. Hünig, B. Becher, and N. Goebels. 2009. Collateral bystander damage by myelindirected CD8+ T cells causes axonal loss. Am. J. Pathol. 175:1160-1166. http://dx.doi.org/10.2353/ajpath.2009.090340
80. Stinchcombe, J.C., and G.M. Griffiths. 2007. Secretory mechanisms in cellmediated cytotoxicity. Annu. Rev. Cell Dev. Biol. 23:495-517. http://dx.doi.org/10.1146/annurev.cellbio.23.090506.123521
81. ter Meulen, V., M.J. Carter, H. Wege, and R. Watanabe. 1984. Mechanisms and consequences of virus persistence in the human nervous system. Ann. N. Y. Acad. Sci. 436:86-97. http://dx.doi.org/10.1111/j.1749-6632 .1984.tb14778.x
82. Walter, G.F., and R.R. Renella. 1989. Epstein-Barr virus in brain and Rasmussen's encephalitis. Lancet. 1:279-280. http://dx.doi.org/10.1016/S0140-6736(89)91292-0
83. Watanabe-Fukunaga, R., C.I. Brannan, N.G. Copeland, N.A. Jenkins, and S. Nagata. 1992. Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis. Nature. 356:314-317. http://dx.doi.org/10.1038/356314a0
84. Whitmire, J.K., J.T. Tan, and J.L. Whitton. 2005. Interferon-γ acts directly on CD8+ T cells to increase their abundance during virus infection. J. Exp. Med. 201:1053-1059. http://dx.doi.org/10.1084/jem.20041463
85. Zhang, S., J. Boyd, K. Delaney, and T.H. Murphy. 2005. Rapid reversible changes in dendritic spine structure in vivo gated by the degree of ischemia. J. Neurosci. 25:5333-5338. http://dx.doi.org/10.1523/JNEUROSCI.1085-05.2005