Type 1 diabetes (T1D) is characterized by massive destruction of insulin-producing β cells by autoreactive T lymphocytes， arising via defective immune tolerance. Therefore， effective anti-T1D therapeutics should combine autoimmunity-preventing and insulin production-restoring properties. We constructed a cell-permeable PDX1-FOXP3-TAT fusion protein (FP) composed of two transcription factors: forkhead box P3 (FOXP3)， the master regulator of differentiation and functioning of self-tolerance-promoting Tregs， and pancreatic duodenal homeobox-1 (PDX1)， the crucial factor supporting β cell development and maintenance. The FP was tested in vitro and in a non-obese diabetic mouse T1D model. In vitro， FP... More
Type 1 diabetes (T1D) is characterized by massive destruction of insulin-producing β cells by autoreactive T lymphocytes， arising via defective immune tolerance. Therefore， effective anti-T1D therapeutics should combine autoimmunity-preventing and insulin production-restoring properties. We constructed a cell-permeable PDX1-FOXP3-TAT fusion protein (FP) composed of two transcription factors: forkhead box P3 (FOXP3)， the master regulator of differentiation and functioning of self-tolerance-promoting Tregs， and pancreatic duodenal homeobox-1 (PDX1)， the crucial factor supporting β cell development and maintenance. The FP was tested in vitro and in a non-obese diabetic mouse T1D model. In vitro， FP converted naive CD4 T cells into a functional "Treg-like" subset， which suppressed cytokine secretion， downregulated antigen-specific responses， and curbed viability of diabetogenic effector cells. In hepatic stem-like cells， FP potentiated endocrine transdifferentiation， inducing expression of Insulin2 and other β lineage-specific genes. In vivo， FP administration to chronically diabetic mice triggered (1) a significant elevation of insulin and C-peptide levels， (2) the formation of insulin-containing cell clusters in livers， and (3) a systemic anti-inflammatory shift (higher Foxp3CD4CD25 T cell frequencies， elevated rates of IL-10-producing cells， and reduced rates of IFN-γ-secreting cells). Overall， in accordance with its design， PDX1-FOXP3-TAT FP delivered both Treg-stabilizing anti-autoimmune and de novo insulin-producing effects， proving its anti-T1D therapeutic potential.
