In human CD4+ T-Cells, omeprazole suppresses proliferation, downregulates V-ATPase, and promotes differentiation toward an autoimmunity-favoring phenotype

Abstract

Background: Proton pump inhibitors (PPIs) represent a commonly prescribed class of medications. Triggered by findings indicating a correlation between PPI usage and susceptibility to infectious or autoimmune diseases, we studied the impact of a pharmacological concentration of omeprazole on human CD4+ T-cells.

Methods: In mixed lymphocyte reactions (MLRs), we analyzed the proliferation index and measured the concentration of key cytokines representative of distinct CD4+ T-cell subsets. In CD4+ T-cells isolated from the MLRs, we evaluated proliferation markers and pathways, the expression of signature transcription factors of CD4+ T-cell subsets, vacuolar H+- ATPase (V-ATPase) levels, and the activation status of AMP-activated kinase (AMPK) and mammalian target of rapamycin complex-1 (mTORC1).

Results: Omeprazole reduced proliferation index in MLRs, and in isolated CD4+ T-cells, it downregulated the proliferation marker Ki-67, possibly mediated by the p53- p21 pathway. Analysis of cytokines and signature transcription factors of CD4+ T-cell subsets indicated that omeprazole decreased T helper 1 (Th1) differentiation, had negligible impact on Th2 differentiation, increased Th17 differentiation, and reduced regulatory T-cell (Treg) differentiation. Omeprazole also decreased V-ATPase, a known target of PPIs and a site for AMPK and mTORC1 activation. Consequently, this led to diminished activation of these kinases, potentially elucidating the mechanism by which omeprazole influences CD4+ T-cell differentiation.

Conclusion: Omeprazole downregulates V-ATPase and inhibits activation of AMPK and mTORC1. As a result, omeprazole suppresses CD4+ T-cell clonal expansion, potentially contributing to the observed association between PPIs and susceptibility to infections. Additionally, it modulates CD4+ T-cell differentiation in a manner that favors autoimmunity.

Keywords: Autoimmunity; Infection; Omeprazole; Proton pump inhibitors; T-cell differentiation; T-cell proliferation.