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Effector Pathway by CD4+ T Cells Selected by I-Ag7 on a Nonobese Diabetic Versus C57BL/6 Genetic Background1
Division of Rheumatology and Immunology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261
IFN-
-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-
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- production was not due to an increase in the amount of IFN-
produced per cell but to an increase in the number of NOD
CD4+ T cells entering the IFN--producing pathway. The
increased IFN- 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- mRNA, an
increase in IL-4 mRNA production, and a significantly decreased
IFN-:IL-4 mRNA transcript ratio compared with NOD cells.
CD4+ T cells from C57BL6 mice also showed significantly
decreased IFN- 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- response, independent
of MHC class II-mediated T cell repertoire selection, even when
compared with a prototypical Th1 strain.
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