HLA-DQ6 (DQB1*0601)-restricted T cells protect against experimental autoimmune encephalomyelitis in HLA-DR3.DQ6 double-transgenic mice by generating anti-inflammatory IFN-gamma.
The human MHC class II genes are associated with genetic susceptibility to multiple sclerosis (MS), a chronic inflammatory demyelinating disease of the CNS of presumed autoimmune origin. These genes encode for proteins responsible for shaping immune response. The exact role of HLA-DQ and -DR genes in disease pathogenesis is not well-understood due to the high polymorphism, linkage disequilibrium, and heterogeneity of human populations. The advent of HLA class II-transgenic (Tg) mice has helped in answering some of these questions. Previously, using single-Tg mice (expressing the HLA-DR or -DQ gene), we showed that proteolipid protein (PLP)(91-110) peptide induced classical experimental autoimmune encephalomyelitis only in DR3.Abeta degrees mice, suggesting that DR3 (DRB1*0301) is a disease susceptible gene in the context of PLP. Human population studies have suggested that HLA-DQ6 (DQB1*0601) may be a protective gene in MS. To test this disease protection in an experimental model, we generated double-Tg mice expressing both HLA-DR3 and -DQ6. Introduction of DQ6 onto DR3-Tg mice led to a decrease in disease incidence on immunization with PLP(91-110) peptide indicating a dominant protective role of DQ6. This protective effect is due to high levels of IFN-gamma produced by DQ6-restricted T cells, which suppressed proliferation of encephalitogenic DR3-restricted T cells by inducing apoptosis. Our study indicates that DQ6 modifies the PLP(91-110)-specific T cell response in DR3 through anti-inflammatory effects of IFN-gamma, which is protective for experimental autoimmune encephalomyelitis. Thus, our double-Tg mouse provides a novel model in which to study epistatic interactions between HLA class II molecules in MS.
Mangalam
Ashutosh
A
Department of Immunology, College of Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Luckey
David
D
Basal
Eati
E
Behrens
Marshall
M
Rodriguez
Moses
M
David
Chella
C
D000818:Animals; D017209:Apoptosis; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000378:metabolism; D006683:HLA-DQ Antigens / Q000276:immunology*; D015803:HLA-DR3 Antigen / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009569:Nitric Oxide / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism
D016207:Cytokines; D006683:HLA-DQ Antigens; C063831:HLA-DQ6 antigen; D015803:HLA-DR3 Antigen; D009569:Nitric Oxide; D007371:Interferon-gamma