The Role of ZEB2 in Human CD8 T Lymphocytes: Clinical and Cellular Immune Profiling in Mowat–Wilson Syndrome

Abstract

The Zeb2 gene encodes a transcription factor (ZEB2) that acts as an important immune mediator in mice, where it is expressed in early-activated effector CD8 T cells, and limits effector differentiation. Zeb2 homozygous knockout mice have deficits in CD8 T cells and NK cells. Mowat–Wilson syndrome (MWS) is a rare genetic disease resulting from heterozygous mutations in ZEB2 causing disease by haploinsufficiency. Whether ZEB2 exhibits similar expression patterns in human CD8 T cells is unknown, and MWS patients have not been comprehensively studied to identify changes in CD8 lymphocytes and NK cells, or manifestations of immunodeficiency. By using transcriptomic assessment, we demonstrated that ZEB2 is expressed in early-activated effector CD8 T cells of healthy human volunteers following vaccinia inoculation and found evidence of a role for TGFß-1/SMAD signaling in these cells. A broad immunological assessment of six genetically diagnosed MWS patients identified two patients with a history of recurrent sinopulmonary infections, one of whom had recurrent oral candidiasis, one with lymphopenia, two with thrombocytopenia and three with detectable anti-nuclear antibodies. Immunoglobulin levels, including functional antibody responses to protein and polysaccharide vaccination, were normal. The MWS patients had a significantly lower CD8 T cell subset as % of lymphocytes, compared to healthy controls (median 16.4% vs. 25%, p = 0.0048), and resulting increased CD4:CD8 ratio (2.6 vs. 1.8; p = 0.038). CD8 T cells responded normally to mitogen stimulation in vitro and memory CD8 T cells exhibited normal proportions of subsets with important tissue-specific homing markers and cytotoxic effector molecules. There was a trend towards a decrease in the CD8 T effector memory subset (3.3% vs. 5.9%; p = 0.19). NK cell subsets were normal. This is the first evidence that ZEB2 is expressed in early-activated human effector CD8 T cells, and that haploinsufficiency of ZEB2 in MWS patients had a slight effect on immune function, skewing T cells away from CD8 differentiation. To date there is insufficient evidence to support an immunodeficiency occurring in MWS patients.

Multiomic profiling reveals metabolic alterations mediating aberrant platelet activity and inflammation in myeloproliferative neoplasms

“…previous studies (23,24), which in turn validated the accuracy of our cell identity assignments (Supplemental Figure 2, L and M). In addition, we observed upregulation of GATA1 and STAT1, important regulators of megakaryopoiesis, in platelets from ET patients, which echoes elevated platelet counts observed in ET patients (Supplemental Figure 2, N and O) (25).…”

Zeb2 drives the formation of CD11c + atypical B cells to sustain germinal centers that control persistent infection

“…MWS is a rare genetic disease in humans [incidence: 1 per 50,000 to 70,000 live births ( 47 )] caused by ZEB2 haploinsufficiency, resulting in developmental abnormalities. Overt immune system defects have not been reported in patients with MWS, and they have normal immunoglobulin levels and responses to vaccinations ( 48 ). However, previous studies also reported that the patients with MWS have dramatically reduced percentages of CD8 + T cell in lymphocytes ( 48 ) and decreased percentages of B cells in lymphocytes, although this did not reach statistical significance ( 49 ).…”

“…Overt immune system defects have not been reported in patients with MWS, and they have normal immunoglobulin levels and responses to vaccinations ( 48 ). However, previous studies also reported that the patients with MWS have dramatically reduced percentages of CD8 + T cell in lymphocytes ( 48 ) and decreased percentages of B cells in lymphocytes, although this did not reach statistical significance ( 49 ). The finding that murine heterozygous Cd23 Cre/+ Zeb2 fl/+ cells had reduced ABC formation in vitro implied that it might be possible to observe a similar phenotype in patients with MWS.…”

ZEB2 regulates the development of CD11c+ atypical B cells

“…MWS is a rare genetic disease in humans (incidence: 1 per 50000-70000 live births (40)) caused by ZEB2 haploinsufficiency resulting in developmental abnormalities. Overt immune system defects have not been reported in MWS patients and they have normal immunoglobulin levels and responses to vaccinations (41). However, previous studies also reported the MWS patients have significantly reduced percentages of CD8 + T cell in lymphocytes (41) and decreased percentages of B cells in lymphocytes though this was not statistically significant (42).…”

“…Overt immune system defects have not been reported in MWS patients and they have normal immunoglobulin levels and responses to vaccinations (41). However, previous studies also reported the MWS patients have significantly reduced percentages of CD8 + T cell in lymphocytes (41) and decreased percentages of B cells in lymphocytes though this was not statistically significant (42). The fact that murine heterozygous CD23 Cre/+ Zeb2 fl/+ cells had reduced ABC formation both in vitro and in vivo implied that it might be possible to observe a similar phenotype in MWS patients.…”