Increased entry into the IFN-gamma effector pathway by CD4(+) T cells selected by I-A(g7) on a nonobese diabetic versus C57BL/6 genetic background

IFN-gamma -mediated Th1 effects play a major role in the pathogenesis of au toimmune diabetes in nonobese diabetic (NOD) mice. We analyzed functional r esponses of CD4(+) T cells from NOD and B6.G7 MHC congenic mice, which shar e the H2(g7) MHC region but differ in their non-MHC genetic background. T c ells from each strain proliferated equally to panstimulation with T cell le ctins as well as to stimulation with glutamic acid decarboxylase 524-543 (s elf) and hen egg lysozyme 11-23 (foreign) I-A(g7)-binding peptide epitopes. Despite comparable proliferative responses, NOD CD4(+) T cells had signifi cantly increased IFN-gamma intracellular/extra-cellular protein and mRNA re sponses compared with B6.G7 T cells as measured by intracellular cytokine a nalysis, time resolved fluorometry, and RNase protection assays. The increa sed IFN-gamma production was not due to an increase in the amount of IFN-ga mma produced per cell but to an increase in the number of NOD CD4(+) T cell s entering the IFN-gamma -producing pathway. The increased IFN-gamma respon se 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 compare d 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 prototypica l Th1 strain.