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 (IKZF1(HI)) and dominant-negative (IKZF1(DN)) 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 (T-H) skewing toward T(H)2, low numbers of regulatory T cells (T-reg), eosinophilia, and abnormal PC proliferation. In contrast to IKZF1(HI) and IKZF1(DH), IKZF1(R183H/C) proteins showed increased DNA binding associated with increased gene expression of T(H)2 and PC differentiation, thus demonstrating that IKZF1(R183H/C) behave as gain-of-function (GOF) alleles. In vitro treatment with lenalidomide, known to degrade IKZF1, corrected T(H)2 and PC abnormalities caused by IKZF1(R183H/C). These data extend the spectrum of pathological mechanisms associated with IKZF1 deficiencies and highlight the role of IKZF1 in late lymphoid differentiation stages.