Increased entry into the IFN-gamma effector pathway by CD4+ T cells selected by I-Ag7 on a nonobese diabetic versus C57BL/6 genetic background.
IFN-gamma-mediated Th1 effects play a major role in the pathogenesis of autoimmune diabetes in nonobese diabetic (NOD) mice. We analyzed functional responses of CD4(+) T cells from NOD and B6.G7 MHC congenic mice, which share the H2(g7) MHC region but differ in their non-MHC genetic background. T cells from each strain proliferated equally to panstimulation with T cell lectins as well as to stimulation with glutamic acid decarboxylase 524-543 (self) and hen egg lysozyme 11-23 (foreign) I-A(g7)-binding peptide epitopes. Despite comparable proliferative responses, NOD CD4(+) T cells had significantly increased IFN-gamma intracellular/extracellular protein and mRNA responses compared with B6.G7 T cells as measured by intracellular cytokine analysis, time resolved fluorometry, and RNase protection assays. The increased IFN-gamma production was not due to an increase in the amount of IFN-gamma produced per cell but to an increase in the number of NOD CD4(+) T cells entering the IFN-gamma-producing pathway. The increased IFN-gamma response in NOD mice was not due to increased numbers of activated precursors as measured by activation/memory markers. B6.G7 lymphoid cells demonstrated an absolute decrease in IFN-gamma mRNA, an increase in IL-4 mRNA production, and a significantly decreased IFN-gamma:IL-4 mRNA transcript ratio compared with NOD cells. CD4(+) T cells from C57BL6 mice also showed significantly decreased IFN-gamma production compared with CD4(+) T cells from NOD.H2(b) MHC-congenic mice (which have an H2(b) MHC region introgressed onto an NOD non-MHC background). Therefore, the NOD non-MHC background predisposes to a quantitatively increased IFN-gamma response, independent of MHC class II-mediated T cell repertoire selection, even when compared with a prototypical Th1 strain.
Koarada
S
S
Division of Rheumatology and Immunology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
Wu
Y
Y
Ridgway
W M
WM
D000818:Animals; D015704:CD4 Antigens / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003208:Concanavalin A / Q000276:immunology; D003433:Crosses, Genetic; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000235:genetics*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000502:physiology*; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D009113:Muramidase / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D012333:RNA, Messenger / Q000378:metabolism; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D015398:Signal Transduction / Q000235:genetics* / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
D015704:CD4 Antigens; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; C407099:I-A g7 antigen; D010446:Peptide Fragments; D012333:RNA, Messenger; D015375:Receptors, Interleukin-2; D003208:Concanavalin A; D007371:Interferon-gamma; C421864:hen egg lysozyme; D009113:Muramidase; D005968:Glutamate Decarboxylase