IL-7 Receptor Basics

IL-7 receptor (IL-7R), binding to its cognate ligand IL-7 (interleukin 7), activates multiple pathways that regulate lymphocyte survival, glucose uptake, proliferation and differentiation. IL-7 (interleukin 7) is an essential cytokine for the development and homeostatic maintenance of T and B lymphocytes.

IL-7 receptor product center

Herein, we will mainly discuss IL-7 receptor (IL-7R) structure, IL-7 receptor (IL-7R) signaling and IL-7 receptor (IL-7R) deficiency.

IL-7 Receptor (IL-7R) Structure

The IL-7 receptor (IL-7R), is a heterodimer consisting of the IL-7R alpha chain (IL-7Rα) and the common gamma (γc) chain.

The human IL-7Rα gene, also known as CD127, is located on chromosome 5p13. It is composed of 8 exons spanning a genomic region of 18 kb. The IL-7Rα gene encodes for an 80-kDa type I membrane glycoprotein of 440 amino acids. The cytoplasmic portion is fundamental for signal transduction, while the extracellular region shares homology with other members of the type I family of cytokine receptors. IL-7Rα is a component of two distinct cytokine receptors, IL-7 and thymic stromal lymphopoietin (TSLP), an IL-7 homolog.

The γc chain, also known as CD132, is shared by IL-2, IL-4, IL-7, IL-9, IL-15 and IL-21 receptor. The γc chain is expressed by most haematopoietic cells.

IL-7 Receptor (IL-7R) Signaling

IL-7 receptor (IL-7R) signaling is initiated when IL-7 crosslinks the extracellular domains of IL-7Rα and γc, bringing together JAK1 and JAK3, which mutually phosphorylate each other, increasing their kinase activity.

The JAK proteins then phosphorylate IL-7Rα, creating a docking site for several signalling molecules. A key signalling molecule is STAT5 (signal transducer and activator of transcription 5), which is phosphorylated following recruitment to IL-7Rα. Phosphorylated STAT5 then dimerizes and translocates to the nucleus where it induces gene transcription.

One significant consequence of IL-7 receptor (IL-7R) signalling is the maintenance of cell survival by promoting a favourable balance of B-cell lymphoma 2 (BCL-2)-family members by increasing expression of the survival proteins BCL-2 and MCL1 (myeloid-cell leukaemia sequence 1), and by redistributing the cell-death proteins BAX (BCL-2-associated X protein) and BAD (BCL-2-antagonist of cell death). thereby, T cells that are deprived of IL-7 die within a few days.

IL-7 also has a role in V(D)J recombination in developing T and B cells, it promotes differentiation of CD8+ T cells in the thymus and induces proliferation of T cells in the periphery.

IL-7 Receptor (IL-7R) Deficiency

IL-7 receptor deficiency, genetic mutations in IL-7 receptor alpha chain (IL-7Rα), are T- B+NK+ severe combined immunodeficiency occurring in both males and females, and account for at least 10% of cases of (severe combined immunodeficiencies) SCID.

Hematopoietic stem cell transplantation is the treatment of choice for this immunodeficiency. In the case of an HLA genoidentical donor, the survival rate reaches 90%.

References

1. Mazzucchelli, R., & Durum, S. K. (2007). Interleukin-7 receptor expression: intelligent design. Nature reviews. Immunology, 7(2), 144.
2. Villa, A., Moshous, D., de Villartay, J. P., Notarangelo, L. D., & Candotti, F. (2014). Severe Combined Immunodeficiencies. In Stiehm's Immune Deficiencies. Elsevier Inc..