Soluble IL-7Rα/sCD127 in Health, Disease, and Its Potential Role as a Therapeutic Agent

Abstract

Soluble cytokine receptors can influence immune responses by modulating the biological functions of their respective ligands. These effects can be either agonistic or antagonistic and a number of soluble cytokine receptors have been shown to play critical roles in both maintenance of health and disease pathogenesis. Soluble IL-7Ra (sCD127) is one such example. With its impact on the IL-7/CD127 pathway, which is fundamental for the development and homeostasis of T cells, the role of sCD127 in health and disease has been extensively studied in recent years. Within this review, the role of sCD127 in maintaining host immune function is presented. Next, by addressing genetic factors affecting sCD127 expression and the associated levels of sCD127 production, the roles of sCD127 in autoimmune disease, infections and cancer are described. Finally, advances in the field of soluble cytokine therapy and the potential for sCD127 as a biomarker and therapeutic agent are discussed.

Serum soluble interleukin-7 receptor alpha levels are negatively correlated with the simultaneous activity of antineutrophil cytoplasmic antibody-associated vasculitis

“…Meanwhile, sIL-7Ra has been reported to amplify IL-7 induced CD8+ T cell proliferation. Therefore, it is reasonable to assume that an increase in the population of CD8+ T cells expressing mIL-7Ra may be affected by enhanced serum sIL-7Ra levels (22). We conclude that serum sIL-7Ra showed an inverse association with the activity of BVAS; therefore, it is believed that this study discovered the clinical potential of serum sIL-7Ra as an additional biomarker to predict the cross-sectional activity of AAV.…”

“…On the other hand, sIL-7Rα is a truncated form of mIL-7Rα that is expressed by alternative splicing of the same encoding genes. Unlike mIL-7Rα, sIL-7Rα has paradoxical dual effects on IL-7: a direct antagonistic effect on IL-7 as a scavenger and an indirect agonistic effect on IL-7 by promoting IL-7 bioactivity (9,22). Given that a high concentration of IL-7 has been reported to reduce the expression of mIL7-Ra, IL-7 may act as a negative regulator of IL-7Rα expression (4,22).…”

“…Unlike mIL-7Rα, sIL-7Rα has paradoxical dual effects on IL-7: a direct antagonistic effect on IL-7 as a scavenger and an indirect agonistic effect on IL-7 by promoting IL-7 bioactivity (9,22). Given that a high concentration of IL-7 has been reported to reduce the expression of mIL7-Ra, IL-7 may act as a negative regulator of IL-7Rα expression (4,22). Herein, in AAV patients with high BVAS, in whom the concentration of IL-7 may be considered high, serum sIL-7Ra was significantly decreased, and the population of CD8+ T cells expressing mIL-7Ra was also significantly lower.…”

Implication of IL-7 receptor alpha chain expression by CD8+ T cells and its signature in defining biomarkers in aging

“…Indeed, IL-7Rα low EM CD8 + T cells are largely antigen-experienced (CD27 − CD28 − ) cells [ 5 ]. The soluble form of IL-7Rα without the transmembrane domain can be generated by alternative splicing [ 42 ] although the membrane bound form of IL-7Rα also may also be cleaved [ 43 ]. Low levels of the membrane bound IL-7Rα on IL-7Rα low EM CD8 + T cells could be from increased production of alternatively spliced soluble IL-7Rα.…”

Antisense modulation of IL7R splicing to control sIL7R expression in human CD4+T cells

“…Specifically, sIL7R is formed by exclusion (skipping) of IL7R exon 6, which encodes the single transmembrane span of IL7R (Goodwin et al, 1990). Although a biological function of sIL7R remains elusive, sIL7R has emerged as a pro-immune factor that promotes self-reactive immune responses that underlie autoimmune disorders, with the strongest evidence in MS (Barros et al, 2021). MS is a demyelinating, autoimmune disorder of the central nervous system (CNS), wherein the immune system attacks and destroys the myelin coatings surrounding axons in the brain and spinal cord, leading to progressive neurodegeneration and disability.…”