A Novel Human Mutation Results in T and NK Cell-driven Immune Dysregulation

Overview

Journal J Exp Med

Specialties Allergy & Immunology
General Medicine

Date 2019 May 2

PMID 31040184

Citations 39

Authors

Isabel Z Fernandez

Ryan M Baxter

Josselyn E Garcia-Perez

Elena Vendrame

Thanmayi Ranganath

Daniel S Kong

Karl Lundquist

Tom Nguyen

Sidney Ogolla

Jennifer Black

Csaba Galambos

James C Gumbart

Noor Dawany

Judith R Kelsen

Edwin F de Zoeten

Ralph Quinones

Hesham Eissa

Michael R Verneris

Kathleen E Sullivan

Rosemary Rochford

Catherine A Blish

Ross M Kedl

Cullen M Dutmer

Elena W Y Hsieh

Affiliations

Soon will be listed here.

Abstract

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-2Rγ subunits, with defects in IL-2Rα and IL-2Rγ 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 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 CD56 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.

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