IKZF2 gene codes for a zinc-finger protein Helios that is an activator and repressor of transcription. Helios knockout mice develop autoimmunity by the age of 6 month. Helios is upregulated in T cells in response to T cell receptor stimulation and it is identified as an important transcription factor in exhausted T cells. Highest expression of Helios is found from regulatory T cells (Treg), where it stabilizes their suppressive phenotype. Though studies in mice suggest that Helios has an important role in controlling immune responses, the full range of its effects in humans remains to be shown. We have identified, to our knowledge, first germline loss of function mutation described in humans with immunodeficiency phenotype.
Characterization of immunophenotype using array of techniques including interactome analysis, flow cytometry, RNA sequencing, and cell cultures.
A Finnish adult was exome sequenced due to hypogammaglobulinemia and heterozygous loss-of function mutation in IKZF2 (Helios) was found. Same variant was also detected from her first degree relative. Both patients had hypothyreosis, but otherwise signs of autoimmunity were relatively mild. The T cell phenotype of patients was proinflammatory and markedly more mature, even senescent. We found the patients’ Treg phenotype to be more inflammatory and Treg numbers were reduced.
In line with data from Helios deficient murine models heterozygous loss of Helios expression in patients leads to more proinflammatory T cell phenotype. This most likely is the result of Helios’ effect on both effector and regulatory T cells.