We developed a novel conditional knockout mouse model in which the PDK1 is specifically ablated by OX40 Cre in a subset of CD4+ effector/memory T cells and Tregs , which are also concomitantly labeled with a fluorescent reporter YFP molecule, enabling tracking of the mutant PDK1-deficient cell populations in vivo. The resultant mice (designated PDK1-CKO) are born healthy similar to conditional heterozygous control mice (PDK1-CHET), but gradually and spontaneously develop symptoms and immune manifestations of human scleroderma- including skin dermatitis, fibrosis and thickening with increased collagen deposition, immune infiltration into the skin, an increase in Th2 effector cells, and elevations in Type 2 and pro-inflammatory cytokines in serum, including IL-4, IL-10, IL-13 and IL-6 also found in sera of human scleroderma. Moreover, the proportion of regulatory T cells is reduced compared to effector T cells, which are mostly activated Th2 cells in lymphoid organs. Transfer of wild type Tregs into PDK1-CKO mice ameliorates skin dermatitis, fibrosis and dampens the Th2 response, and transfer of effector CD4 T cells from PDK-CKO mice into immunodeficient hosts triggers skin pathology. Our results suggest a model for disease development in PDK1-CKO mice: Tregs are functionally impaired, enabling the development of pathogenic YFP+ Th2 effector CD4 T cells which migrate to skin and also promote systemic Th2-driven pathology.
- Copyright © 2013 by The American Association of Immunologists, Inc.