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Journal of immunology

Journal of immunology

IF: 3.4
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IFN-β Pretreatment Alleviates Allogeneic Renal Tubular Epithelial Cell–Induced NK Cell Responses via the IRF7/HLA-E/NKG2A Axis

Published:15 February 2024 DOI: 10.4049/jimmunol.2200941 PMID: 38149913
Xing Zhang,?Junni Wang,?Mowang Wang,?Mengbao Du,?Jianghua Chen,?Limengmeng Wang,?Jianyong Wu

Abstract

Immune checkpoint molecules are promising targets for suppressing the immune response but have received little attention in immune tolerance induction in organ transplantation. In this study, we found that IFN-β could induce the expression of HLA-E as well as PD-L1 on human renal tubular epithelial cell line HK-2 and renal tissue of the C57BL/6 mouse. The JAK/STAT2 pathway was necessary for this process. Upregulation of both HLA-E and PD-L1 was fully abrogated by the JAK1/2 inhibitor ruxolitinib. Signaling pathway molecules, including STAT1, STAT2, mTOR, Tyk2, and p38 MAPK, were involved in HLA-E and PD-L1 upregulation. IRF7 is the key transcription factor responsible for the activation of HLA-E and PD-L1 promoters. Through screening an epigenetic regulation library, we found a natural compound, bisdemethoxycurcumin, enhanced IFN-β-induced HLA-E and PD-L1 expression in?vitro and in?vivo. In PBMC-derived CD56+ NK cells, we found that NKG2A but not PD1 was constitutively expressed, indicating HLA-E/NKG2A as a more potent target to induce tolerance to innate immune cells. Pretreating HK-2 cells by IFN-β significantly attenuated the degranulation of their coincubated NK cells and protected cells from NK-mediated lysis. In conclusion, IFN-β pretreatment could activate HLA-E and PD-L1 transcription through the JAK/STAT/IRF7 pathway and then could protect renal tubular epithelial cells from allogeneic immune attack mediated by NK cells.

Substances (26)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Rapamycin 53123-88-9 C51H79NO13 1034 suppliers $9.00-$6160.00
Rapamycin 53123-88-9 C51H79NO13 1034 suppliers $9.00-$6160.00
Rapamycin 53123-88-9 C51H79NO13 1034 suppliers $9.00-$6160.00
Rapamycin 53123-88-9 C51H79NO13 1034 suppliers $9.00-$6160.00
Fludarabine 21679-14-1 C10H12FN5O4 558 suppliers $5.00-$12512.00
Fludarabine 21679-14-1 C10H12FN5O4 558 suppliers $5.00-$12512.00
Fludarabine 21679-14-1 C10H12FN5O4 558 suppliers $5.00-$12512.00
Fludarabine 21679-14-1 C10H12FN5O4 558 suppliers $5.00-$12512.00
Ruxolitinib 941678-49-5 C17H18N6 460 suppliers $10.00-$2757.40
Ruxolitinib 941678-49-5 C17H18N6 460 suppliers $10.00-$2757.40

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