IDDM GENES AND INTERFERON GAMMA

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DESCRIPTION: (Adapted from the Investigator's abstract): As a component of normal host defense, the Th1 subset of CD4+ T cells promotes inflammatory immune responses that effectively eliminate intracellular pathogens. In insulin-dependent diabetes (IDDM), the finding of biased production of IFN gamma, the principal cytokine produced by Th1 effector cells, suggests that the autoimmune response may be environmentally or genetically programmed to polarize to a destructive Th1 phenotype. The molecular and genetic paths that regulate the evolution of Th1 or Th2 effector subtypes are poorly understood; our studies using transgenic mice with reporter genes controlled by IFN gamma promoter elements indicate a tightly regulated evolution of transcriptional control of IFN gamma gene expression during T helper cell development. The IFN gamma promoter contains separate regulatory elements, which govern gene expression in response to cytokine signaling (IL-12, IL-18) and T cell receptor (TCR) signaling. We have found that NOD CD4 T cells (but not other strains) readily differentiate into the Th1 subset in response to a polyclonal TCR stimulus in the absence of IL-12. This skewed development into the Th1 subset precedes the earliest evidence of clinical disease, is independent of gender, and is reversed by disease resistance genetic loci from the B6 or B10 strain. These data argue that the molecular programming of NOD CD4 T cells skews T cell development towards the Th1 subset independent of the antigen binding properties of the NOD MHC and the nature of the autoantigen recognized by individual T cells. The objectives of this application are to 1) identify aberrant transcriptional or biochemical paths which permit NOD T cells to undergo skewed Th1 differentiation, 2) identify the contribution of disease susceptibility/resistance loci to this skewed Th1 differentiation, 3) identify the contribution of IFN gamma promoter TCR-response elements and IL-l2R/IL-18R-response elements to IFN gamma gene expression during evolution of diabetes, and 4) identify contributions of specific IDD loci to IFN gamma promoter activation in islets during transitions from insulitis to diabetes. These questions are not simply of academic interest. Answers to these questions may make it possible to "re-polarize" immune responses from a destructive Th1 phenotype to a protective Th2 phenotype.