A novel human IL2RB mutation results in T and NK cell-driven immune dysregulation.
Fernandez, Isabel Z. 1,*; Baxter, Ryan M. 1,*; Garcia-Perez, Josselyn E. 1; Vendrame, Elena 2; Ranganath, Thanmayi 2; Kong, Daniel S. 1; Lundquist, Karl 3; Nguyen, Tom 4; Ogolla, Sidney 1; Black, Jennifer 5; Galambos, Csaba 5; Gumbart, James C. 3; Dawany, Noor 6; Kelsen, Judith R. 7; de Zoeten, Edwin F. 4; Quinones, Ralph 8; Eissa, Hesham 8; Verneris, Michael R. 8; Sullivan, Kathleen E. 9; Rochford, Rosemary 1; Blish, Catherine A. 2,10; Kedl, Ross M. 1,**,; Dutmer, Cullen M. 11,**,; Hsieh, Elena W.Y. 1,11,**,
[Article] Journal of Experimental Medicine. 216(6):1255-1267, June 03, 2019.

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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-2R[alpha], IL-2R[beta], and IL-2R[gamma] subunits, with defects in IL-2R[alpha] and IL-2R[gamma] and their downstream signaling effectors resulting in known primary immunodeficiency disorders. Here, we report the first human defect in IL-2R[beta], 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-2R[beta] surface expression and dysregulated IL-2/15 signaling, with an anticipated reduction in regulatory T cells. However, in contrast to the IL-2R[beta]-/- 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-2R[beta] expression and signaling in T and NK cells.

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