Different strategies for producing naturally soluble form of common cytokine receptor gamma chain

Abstract

The common cytokine receptor gamma chain (gamma(c)) plays an essential role in regulating lymphoid homeostasis. In fact, alteration of this gene causes severe immunodeficiency in humans and animals. Although soluble gamma(c) (s gamma(c)) was identified in the late 1990s, much remains unknown about its production. This study describes various mechanisms underlying the generation of s gamma(c) isoforms in different species. Our data demonstrate that mouse gamma(c) and the avian ortholog gamma(c)-a did not generate s gamma(c). Moreover, two mouse isoforms, CRA-a and m gamma(c)-b, encoded by transcripts lacking a transmembrane region by alternative splicing, did not yield s gamma(c). However, in ducks, s gamma(c) was produced from a gamma(c)-b transcript lacking a transmembrane region by alternative splicing. In chickens, s gamma(c) was produced in normal cells and cell lines by proteolytic shedding of the gamma(c)-b isoform containing intron 5, which displayed a relatively high probability of proteolytic cleavage of the ectodomain. This shedding was suppressed by leupeptin, serine and cysteine protease inhibitor. Compared to the chicken ortholog gamma(c)-a, expression of gamma(c)-b mRNA was differentially regulated according to tissue type, developmental stage, and antigen stimulation. These data demonstrate several mechanisms for producing s gamma(c) and suggest a potential role for s gamma(c) in avian lymphoid homeostatic responses to environmental antigens. (C) 2014 Elsevier Ltd. All rights reserved.