We and others have recently investigated patients with type 1 diabetes for the frequency and function of apopulation of regulatory T cells (Treg), characterized by the simultaneous expression of CD4 and CD25. Ourstudies did not support the notion that altered CD4+CD25+ T cell frequencies are associated with type 1diabetes, but rather identified type 1 diabetes related alterations in the functional activities of these cells interms of suppressing effector T (Teff) cell responses in vitro. The need to bring resolution to theaforementioned published discrepancies in frequency and function of Treg in type 1 diabetes, as well asinvestigate the potential for Teff cell defects, would be afforded with expanded studies that include theparameters of age, metabolic control, and disease duration, as well as to define (in association with Projects1 and 2) the cellular and molecular mechanism(s) underlying this defect. Therefore, the overall objective ofProject 3 is to improve our understanding the mechanisms of immune regulation afforded by CD4+CD25+ Tcells, identify their contribution to the pathogenesis of type 1 diabetes, and evaluate the potential of thesecells to serve as a marker for autoimmune disease activity.
Our specific aims are designed to test thehypothesis that Treg cells are functionally defective in type 1 diabetes, as a result of dysregulatedinteractions with APC, Teff, and NKT cells, and that the cellular & molecular basis for this defect resides inpathways controlling the phenotypic signature of Treg including surface CD25, FOXP3, as well as TGFfS.This hypothesis has been formed based on our observations of deficient functional activities of Treg inhuman type 1 diabetes, recent data suggesting the surface expression/stability of CD25 is crucial tomaintaining regulatory homeostasis between Treg and Teff, literature indicating the immunological synapsewith other immune system cells (e.g., DC, NKT cells) may influence the functional activities of Treg, as wellas information suggesting key roles for a limited number of cytokines (e.g., IL-2, IL-10, TGFp) and matrixmetalloproteinases are associated with these regulatory processes. The Project has two specific aims: 1)Identify the influence of age, type 1 diabetes, and metabolic control on the frequency and function ofregulatory T cells defined by co-expression of CD4 and CD25, as well as on the cellular expression of thefork-head transcription factor FoxPS. 2) Define the molecular mechanisms underlying deficiencies inCD4+CD25+ T cell function in subjects with type 1 diabetes. The successful completion of these studiescould provide key information to fill an existing knowledge void regarding the mechanistic interactionsbetween specific cell populations that underlie the failure of immune regulation which results in type 1diabetes.
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