Cellular sources and targets of IFN-gamma-mediated protection against viral demyelination and neurological deficits.
IFN-gamma is an anti-viral and immunomodulatory cytokine critical for resistance to multiple pathogens. Using mice with targeted disruption of the gene for IFN-gamma, we previously demonstrated that this cytokine is critical for resistance to viral persistence and demyelination in the Theiler's virus model of multiple sclerosis. During viral infections, IFN-gamma is produced by natural killer (NK) cells, CD4(+) and CD8(+) T cells; however, the proportions of lymphocyte subsets responding to virus infection influences the contributions to IFN-gamma-mediated protection. To determine the lymphocyte subsets that produce IFN-gamma to maintain resistance, we used adoptive transfer strategies to generate mice with lymphocyte-specific deficiencies in IFN-gamma-production. We demonstrate that IFN-gamma production by both CD4(+) and CD8(+) T cell subsets is critical for resistance to Theiler's murine encephalomyelitis virus (TMEV)-induced demyelination and neurological disease, and that CD4(+) T cells make a greater contribution to IFN-gamma-mediated protection. To determine the cellular targets of IFN-gamma-mediated responses, we used adoptive transfer studies and bone marrow chimerism to generate mice in which either hematopoietic or somatic cells lacked the ability to express IFN-gamma receptor. We demonstrate that IFN-gamma receptor must be present on central nervous system glia, but not bone marrow-derived lymphocytes, in order to maintain resistance to TMEV-induced demyelination.
Murray
Paul D
PD
Department of Immunology, Mayo Clinic and Foundation, Rochester, MN 55905, USA.
McGavern
Dorian B
DB
Pease
Larry R
LR
Rodriguez
Moses
M
D000818:Animals; D000956:Antigens, Viral / Q000032:analysis; D016026:Bone Marrow Transplantation; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D018188:Cardiovirus Infections / Q000150:complications / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D003433:Crosses, Genetic; D003711:Demyelinating Diseases / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D016219:Immunotherapy, Adoptive; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016131:Lymphocyte Subsets / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009103:Multiple Sclerosis; D011597:Psychomotor Performance; D012367:RNA, Viral / Q000032:analysis; D011828:Radiation Chimera; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D013116:Spinal Cord / Q000473:pathology; D017945:Theilovirus / Q000276:immunology / Q000502:physiology*; D000096743:Interferon gamma Receptor
D000956:Antigens, Viral; D007371:Interferon-gamma; D012367:RNA, Viral; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor