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Association Between HLA Class II and TLR4 Regulates HLA-II Stimulated P-selectin Expression and Monocyte Capture to Endothelial Cells

Y. Jin, J. Nevarez-Mejia, E. F. Reed

Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, CA

Meeting: 2021 American Transplant Congress

Abstract number: 215

Keywords: Endothelial cells, HLA antibodies, MHC class II, Rejection

Topic: Basic Science » Histocompatibility and Immunogenetics

Session Information

Session Name: B cell/Antibody and Histocompatibility

Session Type: Rapid Fire Oral Abstract

Date: Monday, June 7, 2021

Session Time: 4:30pm-5:30pm

 Presentation Time: 5:00pm-5:05pm

Location: Virtual

*Purpose: Antibody-mediated rejection (AMR) is a major obstacle for long-term allograft survival. Donor specific HLA antibodies (DSA) contribute to the process of AMR by binding to HLA molecules on endothelial cells (EC) and triggering intracellular signal networks leading to EC activation and microvascular inflammation. However, the mechanisms underlying how HLA-II Ab elicit intracellular signals causing activation of vascular EC are poorly understood. Although HLA-II molecules lack signaling motifs and kinase activity in their short cytoplasmic tail, previous studies reported that MHC class II molecules interact with TLR4 to promote immune responses. We therefore postulated that HLA-II associates with TLR4 to transduce signals leading to EC activation, P-selectin expression and monocyte recruitment to EC.

*Methods: HLA-II molecule expression on primary human aortic EC was induced using recombinant adenovirus pAd/PL-DEST encoding CIITA (Ad-CIITA) an HLA-II transactivator, or pretreated with TNF-α/IFN-γ. HLA-II expression was measured by flow cytometry. HLA-II:TLR4 complex formation was determined by stimulating EC with F(ab’)2 fragments of anti-HLA-II mAb, cell lysates were immunoprecipitated with HLA-II Ab and complex formation was detected by Western Blot. Gene silencing was performed by siRNA transfection. P-selectin expression was detected by cell-based ELISA. Monocyte adhesion to EC measured by fluorescence microscopy and analyzed with CellProfiler.

*Results: Infection of EC with Ad-CIITA or pretreatment of EC with TNF-α and IFN-γ induced a marked increase in HLA-II antigen expression. Ligation of HLA II on EC with antibody triggered molecular association between HLA II and TLR4, stimulated phosphorylation of key signal molecules in the TLR4 pathway including JNK, P38, ERK, and NF-kB. Knockdown of TLR4 or MyD88 with siRNA in EC, but not TRIF siRNA, abrogated the ability of HLA-II to stimulate phosphorylation of these kinases, P-selectin expression and monocyte recruitment.

*Conclusions: These results indicate a mutual dependency between HLA II and TLR4 to stimulate EC P-selectin expression and monocyte recruitment, which may be important in promoting AMR and transplant vasculopathy. Our results provide a novel mechanism for HLA-II Ab-mediated alterations in EC and suggest that disrupting HLA II: TLR4 interactions may be required to achieve optimal efficacy in controlling HLA II Ab-mediated AMR.

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To cite this abstract in AMA style:

Jin Y, Nevarez-Mejia J, Reed EF. Association Between HLA Class II and TLR4 Regulates HLA-II Stimulated P-selectin Expression and Monocyte Capture to Endothelial Cells [abstract]. Am J Transplant. 2021; 21 (suppl 3). https://atcmeetingabstracts.com/abstract/association-between-hla-class-ii-and-tlr4-regulates-hla-ii-stimulated-p-selectin-expression-and-monocyte-capture-to-endothelial-cells/. Accessed May 8, 2025.

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