Loss of IFN-gamma enables the expansion of autoreactive CD4+ T cells to induce experimental autoimmune encephalomyelitis by a nonencephalitogenic myelin variant antigen.
MHC variant peptides are analogues of immunogenic peptides involving alterations of the MHC-binding residues, thereby altering the affinity of the peptide for the MHC molecule. Recently, our laboratory demonstrated that immunization of WT B6 mice with 45D, a low-affinity MHC variant peptide of MOG(35-55), results in significantly attenuated experimental autoimmune encephalomyelitis (EAE), yet IFN-gamma production is comparable to myelin oligodendrocyte glycoprotein (MOG)(35-55)-immunized mice. In light of these findings, we asked whether IFN-gamma was required for the reduced encephalitogenicity of the weak ligand 45D in EAE. In this study, we report that immunization of mice deficient in IFN-gamma or its receptor with 45D exhibit significant EAE signs compared with 45D-immunized wild-type B6 mice. Moreover, 45D-immunized IFN-gamma(-/-) and IFN-gammaR(-/-) mice demonstrate MOG tetramer-positive CD4(+) T cells within the CNS and display substantial numbers of MOG-specific CD4(+) T cells in the periphery. In contrast, wild-type mice immunized with 45D exhibit reduced numbers of MOG-specific CD4(+) T cells in the periphery and lack MOG tetramer- positive CD4(+) T cells in the CNS. Importantly, the increased encephalitogenicity of 45D in mice lacking IFN-gamma or IFN-gammaR was not due to deviation toward an enhanced IL-17-secreting phenotype. These findings demonstrate that IFN-gamma significantly attenuates the encephalitogenicity of 45D and are the first to highlight the importance of IFN-gamma signaling in setting the threshold level of responsiveness of autoreactive CD4(+) T cells to weak ligands.
Sabatino
Joseph J
JJ
Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322, USA.
Shires
John
J
Altman
John D
JD
Ford
Mandy L
ML
Evavold
Brian D
BD
D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D049109:Cell Proliferation; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005260:Female; D006649:Histocompatibility Antigens / Q000276:immunology*; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D020381:Interleukin-17 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein / Q000378:metabolism; D063308:Myelin-Oligodendrocyte Glycoprotein; D017471:Receptors, Interferon / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D000096743:Interferon gamma Receptor
D006649:Histocompatibility Antigens; D007371:Interferon-gamma; D020381:Interleukin-17; D009185:Myelin Proteins; D018992:Myelin-Associated Glycoprotein; D063308:Myelin-Oligodendrocyte Glycoprotein; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor; C571327:Mog protein, mouse