IL-2Rβ (CD122) is essential for IL-2 and IL-15 signaling and for natural killer (NK) and T cell homeostasis. We and others have recently described biallelic loss-of-function IL2RB variants, primarily affecting the extracellular domain, cause immune dysregulation with defects in regulatory T cell (Treg) and NK cell function. These reports highlight growing allelic and functional heterogeneity in IL2RB-associated disease. Here, we describe the first monoallelic intracellular truncating IL-2Rβ variant that acts as a dominant negative, expanding the mechanistic and clinical spectrum of IL2RB deficiency.
To define the impact of this heterozygous variant IL2RB c.819-2_832del (p.W273Cfs*4), we performed flow cytometry–based immunophenotyping, phospho-flow analysis of IL-2/IL-15–induced STAT5 signaling, and ImageStream assessment of IL-2Rβ localization.
A 4-year-old boy presented with lymphadenopathy and Evans syndrome with immune thrombocytopenia (ITP) and moderate autoimmune hemolytic anemia (AIHA) refractory to treatment—intravenous immunoglobulin (IVIG), steroids, eltrombopag, romiplostim, and sirolimus. Flow cytometric analyses of peripheral blood mononuclear cells (PBMC) revealed reduced CD8+ T cell frequency but with normal CD4 T and mildly reduced Tregs. The B cell compartment showed signs of chronic activation/exhaustion (increased CD21low), while overall NK cell numbers were reduced yet enriched for immature cells. Whole exome sequencing (WES) identified a heterozygous IL2RB deletion, resulting in one allele producing a truncated protein predicted to eliminate endocytosis, JAK1 binding, and receptor signaling. STAT5 phosphorylation was intact in response to IL-7 (positive control) but drastically reduced in response to both IL-2 and IL-15. ImageStream analyses demonstrated increased surface expression of truncated IL-2Rβ over wild-type protein on NK and T cells.
The monoallelic IL2RB c.819-2_832del variant acts as a dominant negative, mechanistically resulting in both impaired IL-2Rβ signaling and endocytosis from the membrane and causing immune dysregulation. This work expands the spectrum of IL-2Rβ–associated disease and highlights distinctions among IL-2Rβ loss of function (LOF), hypomorphic, and dominant-negative states, as well as IL-2RA and IL-2Rγ deficiencies.
