The risk-variant rs56258221 at the BACH2-locus associates with skewed polarization of naive CD4+T cells towards pro-inflammatory phenotypes in primary sclerosing cholangitis

Background and Aims The pathogenesis of Primary sclerosing cholangitis (PSC) is still unknown. Intrahepatic naive-like T cell population prone to polarize towards TH17 phenotype and several polymorphisms in immune-related genes has been linked to PSC. We hypothesized that genetic predisposition contributing to T cell phenotype in patients with PSC.

Methods Patients with PSC (n=270) were genotyped for the disease-associated risk variants rs56258221 (BACH2), rs80060485 (FOXP1), rs4147359 (IL2RA) and rs7426056 (CD28). T cell function and phenotype, in vitro polarization and proliferation, microRNA-assays, western blots and single-cell RNA sequencing was performed.

Results Functional in vitro experiments with naive CD4+T cells from patients with PSC and healthy donors (HD) as controls showed increased capacity of PSC-derived cells to convert into pro-inflammatory T Helper 1 (TH1, 50.7% vs. 42.9%, p=0.027) and T Helper 17 (TH17, 5,5% vs. 2,2%, p=0.042) subsets. Moreover, lower conversion rate into induced regulatory T cells (iTREG, 9.6% vs. 17.3%, p=0.022) could be detected. The observed effects were increased in rs56258221 (BACH2) carriers and not seen for the other variants in immune-related genes assessed. Interestingly, single-cell RNA sequencing of the T cell compartment identified a composition skewed towards activated phenotypes in rs56258221-carriers.Reduction of BACH2 on protein level was linked to a strongly increased expression of microRNA 4464, previously imputed to inhibit translation of BACH2.

Conclusion We here present comprehensive data linking the risk variant rs56258221 to the recently described dysregulated T cell phenotype in patients with PSC.

Publication History

Article published online:
18 January 2023