Loss-of-function mutation in IKZF2 leads to immunodeficiency with dysregulated germinal center reactions and reduction of MAIT cells

Abstract

The IKAROS family transcription factors regulate lymphocyte development. Loss-of-function variants in IKZF1 cause primary immunodeficiency, but IKAROS family members IKZF2 and IKZF3 have not yet been associated with immunodeficiency yet. Here, we describe a pedigree with a heterozygous truncating variant in IKZF2, encoding the translational activator and repressor HELIOS which is highly expressed in regulatory T cells and effector T cells, particularly of the CD8+ T cell lineage. Protein-protein interaction analysis revealed that the variant abolished HELIOS dimerizations as well as binding to members of the Mi-2/NuRD chromatin remodeling complex. Patients carrying the IKZF2 variant presented with a combined immunodeficiency phenotype characterized by recurrent upper respiratory infections, thrush and mucosal ulcers, as well as chronic lymphadenopathy. With extensive immunophenotyping, functional assays, and transcriptional analysis we show that reduced HELIOS expression was associated with chronic T cell activation and increased production of pro-inflammatory cytokines both in effector and regulatory T cells. Lymph node histology from patients indicated dysregulated germinal center reactions. Moreover, affected individuals displayed profoundly reduced circulating MAIT cell numbers. In summary, we show that this novel loss-of-function variant in HELIOS leads to an immunodeficiency with signs of immune overactivation.

Updates of cancer hallmarks in patients with inborn errors of immunity

“…As a transcriptional repressor in lymphocytes, Helios, encoded by IKZF2, has a significant role in regulating effector T-cell activity, similar to the previous function described for IKZF1 [103,104].…”

“…As a transcriptional repressor in lymphocytes, Helios, encoded by IKZF2 , has a significant role in regulating effector T-cell activity, similar to the previous function described for IKZF1 [103,104]. Patients with IKZF2 deficiency present with chronic overactivation of proinflammatory cytokine production with this being the most likely driver of tumor predisposition [103] [mainly because of the up-regulation in both interferon-gamma (IFN-γ) and interleukin-2 (IL-2) downstream signaling pathways] [103].…”

“…Patients with IKZF2 deficiency present with chronic overactivation of proinflammatory cytokine production with this being the most likely driver of tumor predisposition [103] [mainly because of the up-regulation in both interferon-gamma (IFN-g) and interleukin-2 (IL-2) downstream signaling pathways] [103]. In this group of patients, a variable clinical phenotype can be observed in different mutation sites [103,105], and lymphoma has been reported in patients with both underlying autosomal dominant and recessive forms of IKZF2 deficiency [103]. Suppressor Of Cytokine Signaling 1 (SOCS1) mutations lead to autoimmune diseases by increasing the JAK-STAT pathway activation with the production of IFN-g, IL-2 and IL-4.…”