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

The common cytokine receptor γ chain (γ_c) plays an essential role in regulating lymphoid homeostasis. In fact, alteration of this gene causes severe immunodeficiency in humans and animals. Although soluble γ_c (sγ_c) was identified in the late 1990s, much remains unknown about its production. This study describes various mechanisms underlying the generation of sγ_c isoforms in different species. Our data demonstrate that mouse γ_c and the avian ortholog γ_c-a did not generate sγ_c. Moreover, two mouse isoforms, CRA-a and mγ_c-b, encoded by transcripts lacking a transmembrane region by alternative splicing, did not yield sγ_c. However, in ducks, sγ_c was produced from a γ_c-b transcript lacking a transmembrane region by alternative splicing. In chickens, sγ_c was produced in normal cells and cell lines by proteolytic shedding of the γ_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 γ_c-a, expression of γ_c-b mRNA was differentially regulated according to tissue type, developmental stage, and antigen stimulation. These data demonstrate several mechanisms for producing sγ_c and suggest a potential role for sγ_c in avian lymphoid homeostatic responses to environmental antigens.