Khattri R, Kasprowicz D, Cox T, et al. J Immunol. 2002;167:6312–6320
Purpose of the Study.
The disorder IPEX (immunodysregulation, polyendocrinopathy, enteropathy, X-linked syndrome) is characterized by enlargement of secondary lymphoid structures, diabetes mellitus beginning in early infancy, and chronic enteropathy. The gene defect was identified in 2001 as FOXP3 on the X chromosome. The FOXP3 gene is a member of the forkhead family of transcription factors, however, the basis for IPEX has remained poorly characterized. Previous groups have shown that the immune system is in a state of chronic activation in these patients with overproduction of cytokines and immunoglobulins, but the relationship of these problems to the FOXP3 mutations has been unclear. This article describes work defining the role of the FOXP3 protein product, scurfin, to the manifestation of T cell expansion.
The authors use mouse models including the scurfy mouse, which has an inactive FOXP3 gene and mice transgenic for overexpression of FOXP3. Flow cytometry and histology are used to characterize changes in peripheral T cells and the T cell compartments in secondary lymphoid structures.
The scurfin protein is expressed in the thymus but had no demonstrable affect on the phenotype of the scurfy mouse. Overexpression of scurfin in the thymus in a normal mouse had modest affects on various thymic subsets but did not induce any changes in the periphery. Overexpression of scurfin globally in normal mice caused decreased T cell proliferation and interleukin (IL)-2 production. Similarly, overexpression of scurfin inhibited cytolytic T cell activity.
The function of scurfin appears to regulate the function and size of the peripheral T cell compartment.
IPEX is an uncommon but nearly always fatal immunodeficiency. Affected boys are often total parenteral nutrition-dependent because of their enteropathy and require very stringent immunosuppression for even short-term survival. Stem cell transplantation may be effective. The importance of this article is in its description of a global overactivity of the T cell compartment. This contributes to our understanding of the pathogenesis of this disorder and reinforces the growing belief that the best management option may be early stem cell transplantation.