A novel human IL2RB mutation results in T and NK cell-driven immune dysregulation

The pleiotropic actions of interleukin-2 (IL-2) are essential for regulation of immune responses and maintenance of immune tolerance. The IL-2 receptor (IL-2R) is composed of IL-2Rα, IL-2Rβ, and IL-2R subunits, with defects in IL-2Rα and IL-2R and their downstream signaling effectors resulting in known primary immunodeficiency disorders. Here, we report the first human defect in IL-2Rβ, occurring in two infant siblings with a homozygous IL2RB mutation in the WSXWS motif, manifesting as multisystem autoimmunity and susceptibility to CMV infection. The hypomorphic mutation results in diminished IL-2Rβ surface expression and dysregulated IL-2/15 signaling, with an anticipated reduction in regulatory T cells. However, in contrast to the IL-2Rβ–/– animal model, which lacks NK cells, these siblings demonstrate an expansion of NK cells, particularly the CD56bright subset, and a lack of terminally differentiated NK cells. Thus, the early-onset autoimmunity and immunodeficiency are linked to functional deficits arising from altered IL-2Rβ expression and signaling in T and NK cells.

Source: The Journal of Experimental Medicine - June 2, 2019 Category: Internal Medicine Authors: Fernandez, I. Z., Baxter, R. M., Garcia-Perez, J. E., Vendrame, E., Ranganath, T., Kong, D. S., Lundquist, K., Nguyen, T., Ogolla, S., Black, J., Galambos, C., Gumbart, J. C., Dawany, N., Kelsen, J. R., de Zoeten, E. F., Quinones, R., Eissa, H., Verneris, Tags: Autoimmunity, Immunodeficiency, Human Disease Genetics Brief Definitive Reports Source Type: research