An Enhancer of the IL-7 Receptor α-Chain Locus Controls IL-7 Receptor Expression and Maintenance of Peripheral T Cells

The IL-7R plays critical roles in lymphocyte development and homeostasis. Although IL-7R expression is strictly regulated during lymphocyte differentiation and the immune response, little is known regarding its in vivo regulation. To address this issue, we established a mouse line with targeted deletion of the conserved non-coding sequence 1 (CNS1) element found 3.6 kb upstream of the IL-7R alpha promoter. We report that IL-7R alpha is expressed normally on T and B cells in thymus and bone marrow of CNS1(-/-) mice except for in regulatory T cells. In contrast, these mice show reduced IL-7R alpha expression in conventional CD4 and CD8 T cells as well as regulatory T, NKT, and gamma delta T cells in the periphery. CD4 T cells of CNS1(-/-) mice showed IL-7R alpha upregulation in the absence of growth factors and IL-7R alpha downregulation by IL-7 or TCR stimulation, although the expression levels were lower than those in control mice. Naive CD4 and CD8 T cells of CNS1(-/-) mice show attenuated survival by culture with IL-7 and reduced homeostatic proliferation after transfer into lymphopenic hosts. CNS1(-/-) mice exhibit impaired maintenance of Ag-stimulated T cells. Furthermore, IL-7R alpha upregulation by glucocorticoids and TNF-alpha was abrogated in CNS1(-/-) mice. This work demonstrates that the CNS1 element controls IL-7R alpha expression and maintenance of peripheral T cells, suggesting differential regulation of IL-7R alpha expression between central and peripheral lymphoid organs.