A soluble form of the murine common γ chain is present at high concentrations in vivo and suppresses cytokine signaling

Abstract

The common gamma-chain (␥c) is a component of the receptors for IL-2, IL-4, IL-7, IL-9, and IL-15 and is essential for their signal transduction. Western blotting and a newly established enzyme-linked immunosorbent assay detected substantial constitutive levels (50-250 ng/mL) of soluble ␥c (s␥c) in sera of murine inbred strains. It was demonstrated that purified immune cells, such as T, B, and natural killer cells, and macrophages released this protein after activation. Transfection experiments with cDNA encoding the fulllength ␥c showed that shedding of the transmembrane receptor led to the release of s␥c. The shedding enzymes, however, appeared to be distinct from those cleaving other cytokine receptors because inhibitors of metalloproteases (eg, TAPI) did not influence s␥c release. In vivo, superantigen-induced stimulation of T cells enhanced s␥c serum concentrations up to 10-fold within 6 hours. Because these findings demonstrated regulated expression of a yet unknown molecule in the immune response, further experiments were performed to assess the possible function(s) of s␥c. A physiological role of s␥c was indicated by its capacity to specifically inhibit cell growth induced by ␥c-dependent cytokines. Mutational analysis revealed that the Cterminus and the WSKWS motif are essential for the cytokine inhibitory effect of the s␥c and for binding of the molecule to cytokine receptor-expressing cells. Thus, competitive displacement of the transmembrane ␥c by excess s␥c is the most likely mechanism of cell growth inhibition. It was implied that naturally produced s␥c is a negative modulator of ␥c-dependent cytokines. IntroductionThe murine common gamma-chain (␥c) is a 64-kd type 1 transmembrane protein of the cytokine receptor family. 1 Although the ␥c alone is unable to bind to cytokines, it has been shown to be an essential component of the cell surface receptor complexes of IL-2, IL-4, IL-7, IL-9, and IL-15. 1 Interaction of the respective cytokines with the ␥c within the receptor complexes results in the activation of the Janus kinase JAK3, 2 which subsequently interacts with Pyk2, a member of focal adhesion tyrosine kinases, leading to the phosphorylation of this protein. 3 Recent studies have shown that the ␥c is critical for lymphoid development because genetic defects of either this molecule 4 or JAK3 5 in humans or targeted deletions of the ␥c 6,7 or JAK3 8-10 in mice severely impair the development of T and B cells, leading to severe combined immune deficiency syndromes (SCID). 11 Soluble cytokine receptors and growth factor receptors are present as immunomodulatory molecules in body fluids of humans and mice (reviewed in references 12 and 14). Two major nonexclusive mechanisms are responsible for the generation of soluble cytokine receptors: proteolytic cleavage of transmembrane receptors catalyzed mostly by metalloproteases [15][16][17][18][19] or de novo synthesis of alternatively spliced mRNAs encoding soluble receptor molecules lacking a transmembrane domain. [20][21][22][23][24][25][26][27][28] ...

The common γ-chain cytokine receptor: tricks-and-treats for T cells

“…These results correlated with observations in humans, where synovial fluids of rheumatoid arthritis patients or sera of Crohn’s disease patients showed high levels of sγc proteins [130,131]. Importantly, while sγc proteins had been previously described [130,132], it was not known whether increased sγc expression is the cause or consequence of inflammatory autoimmune disease. Since sγc is expressed by activated T cells and sγc promotes inflammatory Th17 cell differentiation, these findings suggest that sγc is pro-inflammatory and contributes to the severity of inflammatory diseases.…”

Activated T Cells Secrete an Alternatively Spliced Form of Common γ-Chain that Inhibits Cytokine Signaling and Exacerbates Inflammation

“…In agreement with our perspective, soluble γc is highly expressed under inflammatory conditions in both humans and mice. Soluble γc was abundantly expressed in synovial fluid of patients with rheumatoid arthritis and also highly induced in mice challenged with L. major (Meissner et al, 2001; Nishio et al, 2001). We also found that EAE disease outcome and in vivo inflammatory responses were exacerbated in sγc Tg mice.…”

Cloning and Characterization of IL-22 Binding Protein, a Natural Antagonist of IL-10-Related T Cell-Derived Inducible Factor/IL-22

“…3 and unpublished results from our laboratory), suggesting that IL-22 might have pleiotropic activities during inflammatory or immune responses. Although most soluble cytokine receptors are expressed at low levels under resting conditions, their production is often enhanced by activation of T cells or monocytes (14,15,20). Soluble receptors are also sometimes induced by their own ligand as a negative feedback mechanism (14,15).…”