Gain-of-function variants in humans cause immune dysregulation associated with abnormal T/B cell late differentiation.

IKZF1/IKAROS is a key transcription factor of lymphocyte development expressed throughout hematopoiesis. Heterozygous germline haploinsufficient () and dominant-negative () variants in humans cause B cell immune deficiency and combined immunodeficiency. Here, we identified previously unidentified heterozygous variants (R183C/H) located in the DNA binding domain in eight individuals with inflammatory, autoimmune, allergic symptoms, and abnormal plasma cell (PC) proliferation. Leukocytes of patients exhibited specific defects including impaired IL-2 production by T cells, T helper (T) skewing toward T2, low numbers of regulatory T cells (T), eosinophilia, and abnormal PC proliferation. In contrast to IKZF1 and IKZF1, IKZF1 proteins showed increased DNA binding associated with increased gene expression of T2 and PC differentiation, thus demonstrating that behave as gain-of-function (GOF) alleles. In vitro treatment with lenalidomide, known to degrade IKZF1, corrected T2 and PC abnormalities caused by IKZF1. These data extend the spectrum of pathological mechanisms associated with deficiencies and highlight the role of IKZF1 in late lymphoid differentiation stages.