IL2RB maintains immune harmony

Abstract

How the IL-2 receptor β-chain specifically shapes immunity has remained enigmatic. In this issue of JEM, Zhang et al. (https://doi.org/10.1084/jem.20182304) and Fernandez et al. (https://doi.org/10.1084/jem.20182015) independently report the first observations of autosomal recessive mutations in IL2RB, revealing a requirement for IL2RB in immunity and peripheral immune tolerance.

Insights from Tessa M. Campbell and Yenan T. Bryceson.

An illustrative representation of genetic deficiencies comparable to the IL2RB deficiencies reported by Zhang et al. (2019) and Fernandez et al. (2019). Genes are clustered by affiliation with presentation of autoimmune disease (left, blue) or defective viral immunity (right, orange), with increasing severity depicted by proximity to the center. IPEX syndrome (caused by mutations in FOXP3) is a hallmark autoimmune disorder, occurring through a lack of regulatory T cells. In this issue, it is reported that patients with IL2RB mutations presented with an IPEX-like syndrome and viral susceptibility. Similarly, patients with deficiencies in IL2RA, DOCK8, CTLA4, and ITCH have been described with IPEX-like disease. IL-2Rβ forms a signaling complex with the common γ-chain, and deficiencies in IL2RG cause X-SCID, which imparts extreme susceptibility to viral infection. SCID is also associated with deficiencies in JAK3 (which transmits signals from the γ-chain) as well as IL7RA mutations. Finally, STAT5 transduces signals downstream of IL-2Rβ (among other receptors), with deficiencies in STAT5B involving autoimmune presentation and some increased susceptibility to viral infection. Human deficiencies in STAT5A have yet to be identified.

A summary of the relative expression and functional capacity of the IL2RB mutations described by Zhang et al. (2019) and Fernandez et al. (2019) in this issue of JEM, compared with WT IL-2Rβ (+++, high; ++, moderate; +, low; –, negligible).