Transgenic expression of Theiler's murine encephalomyelitis virus genes in H-2(b) mice inhibits resistance to virus-induced demyelination.
We investigated the role of the immune system in protecting against virus-induced demyelination by generating lines of transgenic B10 (H-2(b)) congenic mice expressing three independent contiguous coding regions of the Theiler's murine encephalomyelitis virus (TMEV) under the control of a class I major histocompatibility complex (MHC) promoter. TMEV infection of normally resistant B10 mice results in virus clearance and development of inflammatory demyelination in the spinal cord. Transgenic expression of the viral capsid genes resulted in inactivation of virus-specific CD8(+) T lymphocytes (class I MHC immune function) directed against the relevant peptides, but it did not affect production of virus capsid-specific antibodies or lymphocyte proliferation to the virus antigen (class II MHC immune functions). Following intracerebral infection with TMEV, all three lines of mice survived the acute encephalitis but transgenic mice expressing VP1 (or the cluster of virus capsid proteins [VP4, VP2, and VP3] mapping to the left of VP1 in the TMEV genome) developed virus persistence and subsequent demyelination in spinal cord white matter. Transgenic mice expressing noncapsid proteins mapping to the right of VP1 (2A, 2B, 2C, 3A, 3B, 3C, and 3D) cleared the virus and did not develop demyelination. These results are consistent with the hypothesis that virus capsid gene products of TMEV stimulate class I-restricted CD8(+) T-cell immune responses, which are important for virus clearance and for protection against myelin destruction. Presented within the context of self-antigens, inactivation of these cells by ubiquitous expression of relevant virus capsid peptides partially inhibited resistance to virus-induced demyelination.
Lin
Xiaoqi
X
Department of Neurology, University of Chicago Medical Center, Chicago, Illinois 60637, USA.
Njenga
M Kariuki
MK
Johnson
Aaron J
AJ
Pavelko
Kevin D
KD
David
Chella S
CS
Pease
Larry R
LR
Rodriguez
Moses
M
D000818:Animals; D000914:Antibodies, Viral / Q000097:blood; D001921:Brain / Q000473:pathology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002213:Capsid / Q000235:genetics* / Q000378:metabolism*; D003711:Demyelinating Diseases / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D004198:Disease Susceptibility; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D012720:Severity of Illness Index; D013116:Spinal Cord / Q000473:pathology / Q000821:virology; D017945:Theilovirus / Q000235:genetics* / Q000502:physiology; D019076:Transgenes / Q000235:genetics / Q000502:physiology*
D000914:Antibodies, Viral; D015395:Histocompatibility Antigens Class I