RESUMEN

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-2Rß, 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-2Rß, 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-2Rß surface expression and dysregulated IL-2/15 signaling, with an anticipated reduction in regulatory T cells. However, in contrast to the IL-2Rß-/- 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-2Rß expression and signaling in T and NK cells.

Asunto(s)

Subunidad beta del Receptor de Interleucina-2/genética , Células Asesinas Naturales/inmunología , Mutación/genética , Linfocitos T/inmunología , Autoinmunidad/genética , Compartimento Celular , Proliferación Celular/genética , Infecciones por Citomegalovirus/genética , Infecciones por Citomegalovirus/inmunología , Homocigoto , Humanos , Inmunofenotipificación , Interleucina-15/metabolismo , Interleucina-2/metabolismo , Subunidad beta del Receptor de Interleucina-2/química , Modelos Moleculares , Fenotipo , Hermanos , Transducción de Señal , Resultado del Tratamiento