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 ^DN , 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.