Gain-of-function IKZF1 variants in humans cause immune dysregulation associated with abnormal T/B cell late differentiation

Akihiro Hoshino (1) , David Boutboul , Yuan Zhang , Hye Sun Kuehn , Jerôme Hadjadj , Nihal Özdemir , Tiraje Celkan , Christoph Walz , Capucine Picard , Christelle Lenoir , Nizar Mahlaoui , Christoph Klein , Xiao Peng , Antoine Azar , Erin Reigh , Morgane Cheminant , Alain Fischer , Frédéric Rieux-Laucat , Isabelle Callebaut (2) , Fabian Hauck , Joshua Milner , Sergio Rosenzweig , Sylvain Latour

1 Imagine - U1163 - Imagine - Institut des maladies génétiques (IHU)
2 IMPMC - Institut de minéralogie, de physique des matériaux et de cosmochimie

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.

Domaines: Sciences du Vivant [q-bio]

Akihiro Hoshino, David Boutboul, Yuan Zhang, Hye Sun Kuehn, Jerôme Hadjadj, et al.. Gain-of-function IKZF1 variants in humans cause immune dysregulation associated with abnormal T/B cell late differentiation. Science Immunology, 2022, 7 (69), ⟨10.1126/sciimmunol.abi7160⟩. ⟨hal-03864168⟩