Gain-of-function IKZF1 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 IKZF1 haploinsufficient (IKZF1HI) and dominant-negative (IKZF1DN) variants in humans cause B cell immune deficiency and combined immunodeficiency. Here, we identified previously unidentified heterozygous IKZF1 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 (TH) skewing toward TH2, low numbers of regulatory T cells (Treg), eosinophilia, and abnormal PC proliferation. In contrast to IKZF1HI and IKZF1DN, IKZF1R183H/C proteins showed increased DNA binding associated with increased gene expression of TH2 and PC differentiation, thus demonstrating that IKZF1R183H/C behave as gain-of-function (GOF) alleles. In vitro treatment with lenalidomide, known to degrade IKZF1, corrected TH2 and PC abnormalities caused by IKZF1R183H/C. These data extend the spectrum of pathological mechanisms associated with IKZF1 deficiencies and highlight the role of IKZF1 in late lymphoid differentiation stages.