The Biology of Autoimmune Response in the Scurfy Mice that Lack the CD4+Foxp3+ Regulatory T-Cells

Abstract

Due to a mutation in the Foxp3 transcription factor, Scurfy mice lack regulatory T-cells that maintain self-tolerance of the immune system. They develop multi-organ inflammation (MOI) and die around four weeks old. The affected organs are skin, tail, lungs and liver. In humans, endocrine and gastrointestinal inflammation are also observed, hence the disease is termed IPEX (Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked) syndrome. The three week period of fatal MOI offers a useful autoimmune model in which the controls by genetics, T-cell subsets, cytokines, and effector mechanisms could be efficiently investigated. In this report, we will review published work, summarize our recent studies of Scurfy double mutants lacking specific autoimmune-related genes, discuss the cellular and cytokine controls by these genes on MOI, the organ-specificities of the MOI controlled by environments, and the effector mechanisms regulated by specific Th cytokines, including several newly identified control mechanisms for organ-specific autoimmune response.

Figure 1

A schematic representation of how IL-2 controls the skin and lung inflammation in Sf mice. (A) In the Treg-deficient mice, tissue or environmental Ag are picked up and processed by the dendritic cells (DC), which go to the draining LN and are presented to the Th-cells that have specificity for the Ag. Without Treg and in the presence of IL-2, both Th1 and Th2 responses are expanded. TRG essential for Th cells to go to skin and lungs are induced in both subsets, which then travel to the skin and lungs to induce inflammation; (B) In the Sf.Il2^−/− mice, the processed Ag on DC failed to induce a Th2 response due to the absence of IL-2, which is required for Th2 expansion. More importantly, IL-2 is required for the induction of a panel of TRG required for the Th cells to travel to the skin and lungs. IL-2 is not required for the induction of TRG needed for liver inflammation and colitis; (C) In the Sf.Il4^−/− mice, the processed Ag on DC induce Th1 response and but the expression of IL-4-, IL-5-, and IL-13-Th2 cells are not expressed or are strongly inhibited. We do not know if they were activated by IL-2. However, the TRG required for skin and lung inflammation are induced in the Th cells by the presence of IL-2. These Th cells are capable of causing skin and lung inflammation; (D) In the Sf.Ifng^−/− mice, the processed Ag on DC induced both IL-2-producing Th1 cells and IL-4-producing Th2 cells. Although lacking IFN-γ has a general effect (such as recruitment of leukocytes and enhancing Ag-presentation on inflammation), skin and lung inflammation eventually developed because the IL-2-controlled TRG are induced in the activated Th1 and Th2 subsets.