Increased Entry into the IFN-γ Effector Pathway by CD4+ T Cells Selected by I-Ag7 on a Nonobese Diabetic Versus C57BL/6 Genetic Background

Abstract

IFN-γ-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 H2g7 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-Ag7-binding peptide epitopes. Despite comparable proliferative responses, NOD CD4+ T cells had significantly increased IFN-γ 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-γ production was not due to an increase in the amount of IFN-γ produced per cell but to an increase in the number of NOD CD4+ T cells entering the IFN-γ-producing pathway. The increased IFN-γ 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-γ mRNA, an increase in IL-4 mRNA production, and a significantly decreased IFN-γ:IL-4 mRNA transcript ratio compared with NOD cells. CD4+ T cells from C57BL6 mice also showed significantly decreased IFN-γ production compared with CD4+ T cells from NOD.H2b MHC-congenic mice (which have an H2b MHC region introgressed onto an NOD non-MHC background). Therefore, the NOD non-MHC background predisposes to a quantitatively increased IFN-γ response, independent of MHC class II-mediated T cell repertoire selection, even when compared with a prototypical Th1 strain.

Increased Nonobese Diabetic Th1:Th2 (IFN-γ:IL-4) Ratio Is CD4+ T Cell Intrinsic and Independent of APC Genetic Background

“…As we previously published, we have found no evidence that the NOD T cell abnormality was due to increased preactivated or memory autoreactive T cells in the NOD periphery in these 8-wkold mice (35). The results predict that the same phenotype should be found in a nondiabetes prone strain with the NOD non-MHC background.…”

“…Furthermore, this phenotype was mapped near to the Idd5 and Idd13 loci (34). We have recently shown that T cells selected by I-A g7 on an NOD, but not B6, genetic background demonstrated increased entry into the IFN-␥ effector pathway (35). The role of the NOD non-MHC genetic background was confirmed by showing that T cells from NOD.H2…”

Either IL-2 or IL-12 Is Sufficient to Direct Th1 Differentiation by Nonobese Diabetic T Cells

“…Evidence suggests that ␤ cell destruction is mediated, at least in part, by effector CD4 ϩ T cells that preferentially secrete IFN-␥ and TNF-␣ (18,19). NOD CD4 ϩ T cells have been shown to have an increased propensity to become effector Th1 cells in tissue culture assays (20). We wanted to determine whether Th1 differentiation by NOD T cells had the same cytokine requirements as found in other strains.…”

Long-range histone acetylation of the Ifng gene is an essential feature of T cell differentiation

“…Studies in tissue culture models, by us and others, demonstrate that, in contrast to other murine strains, CD4 ϩ T cells from the autoimmune prone nonobese diabetic (NOD) strain are genetically programmed to use IL-2 as a driving cytokine to differentiate into IFN-␥-producing effector T cells (21)(22)(23). Thus, an antigen stimulus is sufficient to drive both T cell proliferation and Th1 differentiation.…”