Abstract
The interleukin-2 receptor γ (IL-2Rγ, or γc) is a crucial component of several cytokine receptor complexes. Deficiencies in γc lead to X-linked severe combined immunodeficiency (X-SCID), characterized by recurrent infections due to the absence or dysfunction of T and NK cells, and nonfunctional B cells. Missense variants in the γc extracellular region are linked to atypical X-SCID with normal counts of T, B, and NK cells and less severe symptoms, yet the underlying cellular and molecular mechanisms are not well understood. This study describes a case of atypical X-SCID with a missense variant (c.420 A > T, p.R140S) in the γc extracellular domain, associated with recurrent bacterial, fungal, and viral infections. We found that the R140S variant leads to reduced surface expression and variably affects cytokine receptor signaling. Specifically, STAT5 phosphorylation and proliferation in CD4+ T and CD8+ T cells are impaired in response to IL-7, a cytokine essential for T cell survival, proliferation and function. Notably, γcR140S predominantly localizes to the endoplasmic reticulum, in contrast to WT γc, which is found in acidic compartments. Despite this mislocalization, γcR140S does not trigger unfolded protein responses, and its protein stability and degradation pathways remain unaffected. Nevertheless, cells expressing high levels of γcR140S exhibited a competitive disadvantage in culture compared to those expressing WT γc, resulting in the enrichment of cells expressing lower levels of γcR140S. These findings extend our understanding of how mutations in the extracellular domain of γc can lead to reduced protein expression and influence the pathophysiology of atypical X-SCID.