IL‐7 induces clathrin‐mediated endocytosis of CD127 and subsequent degradation by the proteasome in primary human CD8 T cells

Abstract

Interleukin-7 (IL-7), a key immunoregulatory cytokine, plays an essential role in peripheral T-cell homeostasis and function. Signaling via the IL-7 receptor is tightly regulated and we and others have shown IL-7 provides negative feedback on its own signaling by downregulating expression of the IL-7 receptor alpha-chain (CD127) through both suppression of CD127 gene transcription and by internalization of existing CD127 proteins from the cell membrane. We show here for the first time in primary human CD8 T cells that upon stimulation with IL-7, CD127 is internalized through clathrin-coated pits, a process dependent on both lipid-raft formation and the activity of dynamin. As visualized by confocal microscopy, CD127 shows increased co-localization with clathrin within 5 min of IL-7 stimulation and within 15-30 min is seen in multiple intracellular punctae co-localizing with the early endosomal marker EEA1. By 2 h after addition of IL-7, CD127 staining associates with the late endosomal marker RAB7 and with the proteasomal 20S subunit. By inducing receptor internalization and translocation from early endosomes to the proteasome, IL-7 directly influences its receptor density on the cell surface and thus regulates the intensity of its own signaling cascades. Given the important role IL-7 plays in T-cell development, homeostasis and function, deciphering how expression of its receptor is controlled on the cell surface is essential in understanding how T-cell activity can be regulated in different microenvironments and in response to different pathogens.

Compartment-specific distribution of human intestinal innate lymphoid cells is altered in HIV patients under effective therapy

“…This was a somewhat counterintuitive finding since IL-7 has been shown to induce receptor internalization in CD8(+) T cells [27]. Thus, we next tested whether IL-7 mediated regulation of CD127 expression in ILCs might differ from that in CD8(+) T cells.…”

Large-Scale Integrative Analysis of Epigenetic Modifications Induced by Isotretinoin, Doxycycline and Metronidazole in Murine Colonic Intestinal Epithelial Cells

“…Pedrotti et al described local intestinal effects on lamina propria cells after systemic changes of IL-12 levels [40]. Thus, it is tempting to speculate that the previously described decrease of systemic IL-12p40 levels is affecting local IECs by up-regulating IL-12rb1 through a negative feedback mechanism that has been described for IL-7/IL-7R on T-cells [41,42]. The effects of an increased expression of IL-12rb1 in IECs have not yet been studied.…”

Interleukin-7 receptor α-chain haplotypes differentially affect soluble IL-7 receptor and IL-7 serum concentrations in children with type 1 diabetes

“…Differential IL‐7‐availability may affect T cell functions including mIL‐7R internalization and cytokine expression in autoimmune diseases . Consequently, we recruited a second cohort of children with T1D ( n = 42; mean age 10.6 years; range 3.0‐16.5 years) and performed functional T cell analyses in children characterized for IL‐7/sIL‐7R serum levels.…”

“…The mIL‐7R is expressed on naïve and memory T cell subsets . On IL‐7 binding, the mIL‐7R complex is rapidly internalized and partly degraded . Because naïve and memory T cells require IL‐7 for homeostatic proliferation, the quantity of these T cell subsets is hypothesized to regulate IL‐7 serum levels …”