Genetic control of the inflammatory T-cell response in regulatory T-cell deficient scurfy mice

Abstract

IPEX (Immunodysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome is a rare, recessive disorder in patients with mutations in the foxp3 gene, the normal expression of which is required for the generation of functional regulatory T-cells. Scurfy mice also bear a mutation in the foxp3, and like IPEX patients, spontaneously develop multi-organ inflammation. As reviewed herein, breeding immune response genes into Scurfy mice has provided useful insight into how the inflammatory T-cell response is regulated in the absence of regulatory T-cells and post regulatory T-cell checkpoint. Of particular interest are those that preferentially affect the inflammatory T-cell response in an "apparent" organ-specific manner, implying that specific mechanisms of control exist for individual organs during multi-organ inflammation.

Figure 1

IL-2 controls trafficking receptor expression for skin and lung inflammation. In the Treg-deficient Sf mice (left panel), both Th1 and Th2 responses are strongly developed in the draining lymph nodes (LN). In the presence of IL-2, receptors for trafficking, chemotaxis, and retention for skin and lungs are induced on CD4⁺ T-cells, allowing them to enter target organs and induce inflammation. In the absence of IL-2 as in Sf.Il2^−/− mice (right panel), these receptors are not expressed and despite having an up-regulated Tinf response, the CD4⁺ T-cells cannot enter the target organs to induce inflammation.

Figure 2

Chemokine expression controls SMG inflammation. The SMG in Sf mice is free of inflammation despite the fact that the Sf lymph nodes (LN) contain CD4⁺ T-cells capable of inducing SMG inflammation upon transferring into Rag1^−/− recipients. The SMG of Sf is severely under-developed and may not produce sufficient chemokines to attract CD4⁺ T-cells to induce inflammation (left panel). Oral application of LPS or poly-I:C up-regulates chemokine expression in SMG, allowing entrance of the CD4⁺ T-cells to induce inflammation (right panel).