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Loss of IFN-gamma enables the expansion of autoreactive CD4+ T cells to induce experimental autoimmune encephalomyelitis by a nonencephalitogenic myelin variant antigen.
J Immunol. 2008 Apr 01; 180(7):4451-7.JI

Abstract

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.

Authors+Show Affiliations

Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

18354166

Citation

Sabatino, Joseph J., et al. "Loss of IFN-gamma Enables the Expansion of Autoreactive CD4+ T Cells to Induce Experimental Autoimmune Encephalomyelitis By a Nonencephalitogenic Myelin Variant Antigen." Journal of Immunology (Baltimore, Md. : 1950), vol. 180, no. 7, 2008, pp. 4451-7.
Sabatino JJ, Shires J, Altman JD, et al. Loss of IFN-gamma enables the expansion of autoreactive CD4+ T cells to induce experimental autoimmune encephalomyelitis by a nonencephalitogenic myelin variant antigen. J Immunol. 2008;180(7):4451-7.
Sabatino, J. J., Shires, J., Altman, J. D., Ford, M. L., & Evavold, B. D. (2008). Loss of IFN-gamma enables the expansion of autoreactive CD4+ T cells to induce experimental autoimmune encephalomyelitis by a nonencephalitogenic myelin variant antigen. Journal of Immunology (Baltimore, Md. : 1950), 180(7), 4451-7.
Sabatino JJ, et al. Loss of IFN-gamma Enables the Expansion of Autoreactive CD4+ T Cells to Induce Experimental Autoimmune Encephalomyelitis By a Nonencephalitogenic Myelin Variant Antigen. J Immunol. 2008 Apr 1;180(7):4451-7. PubMed PMID: 18354166.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Loss of IFN-gamma enables the expansion of autoreactive CD4+ T cells to induce experimental autoimmune encephalomyelitis by a nonencephalitogenic myelin variant antigen. AU - Sabatino,Joseph J,Jr AU - Shires,John, AU - Altman,John D, AU - Ford,Mandy L, AU - Evavold,Brian D, PY - 2008/3/21/pubmed PY - 2008/5/31/medline PY - 2008/3/21/entrez SP - 4451 EP - 7 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J. Immunol. VL - 180 IS - 7 N2 - 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. SN - 0022-1767 UR - https://www.unboundmedicine.com/medline/citation/18354166/Loss_of_IFN_gamma_enables_the_expansion_of_autoreactive_CD4+_T_cells_to_induce_experimental_autoimmune_encephalomyelitis_by_a_nonencephalitogenic_myelin_variant_antigen_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=18354166 DB - PRIME DP - Unbound Medicine ER -