Absence of DAP12 Expression by Donor Liver-Derived Dendritic Cells Enhances Their Contact with T Cells in Host Secondary Lymphoid Tissue: Implications for Abrogation of MHC-mismatched Liver Transplant Tolerance in Mice
University of Pittsburgh, Pittsburgh, PA
Meeting: 2022 American Transplant Congress
Abstract number: 488
Keywords: Liver transplantation, Mice, Tolerance
Topic: Basic Science » Basic Science » 03 - Antigen Presentation / Allorecognition / Dendritic Cells
Session Information
Session Name: Antigen Presentation and Costimulation
Session Type: Rapid Fire Oral Abstract
Date: Tuesday, June 7, 2022
Session Time: 3:30pm-5:00pm
Presentation Time: 4:40pm-4:50pm
Location: Hynes Room 309
*Purpose: Multiphoton intravital microscopy is a high-resolution, real-time, fluorescence imaging technique that enables study of interactions between cells in their native, 3-dimensional environment including organ explants. DNAX activating protein of 12kDa (DAP12) is a homodimeric, immunoreceptor tyrosine-based activation motif (ITAM)-bearing transmembrane adaptor molecule. Signaling through DAP12 in response to extracellular glycoproteins and lipids negatively regulates Toll-like receptor (TLR) responses in myeloid cells and may protect against TLR ligand–induced pro-inflammatory responses. While liver allografts from WT donors are accepted without immunosuppressive therapy, those from DAP12 -/- donors are rejected acutely. Moreover, DAP12-deficient liver DC show enhanced expression of MHC class II and costimulatory molecules and augmented ability to prime alloreactive T cells in vivo. Our aim was to assess the role of DAP12 expression by MHC-mismatched liver transplant-derived DC on their interactions with T cells in host spleens using multiphoton intravital microscopy.
*Methods: Orthotopic allogenic liver transplantation was performed from B6.CD11c-YFP (WT) or B6.DAP12-/-.CD11c-YFP (DAP12KO; H2b) donors to wild-type C3H (H2k) recipients, without immunosuppressive therapy. Explanted spleen from recipients was imaged 1 day after liver transplantation. Interactions between donor-derived liver DCs and both host CD4 and CD8 T cells were imaged and analyzed.
*Results: Donor-derived liver DCs were readily detected in the recipient`s spleen 1 day after transplantation, but were undetectable on day 3. While liver DCs from DAP12KO grafts exhibited the same frequency of contacts as those from WT B6 grafts with host CD4+ and CD8+ T cells, DCs from DAP12 KO grafts had significantly and specifically prolonged interactions with CD8+ T cells than those from WT grafts (P< 0.01).
*Conclusions: Our novel intravital imaging data indicate that DAP12 expression by donor-liver-derived DCs plays an important role in limiting the duration of contact between these important APCs with host CD8+ T cells. This is consistent with enhanced anti-donor reactivity and abrogation of tolerance in recipients of DAP12-/- liver allografts.
To cite this abstract in AMA style:
Nakano R, Gutierrez APerez, Camirand G, Geller DA, Thomson AW. Absence of DAP12 Expression by Donor Liver-Derived Dendritic Cells Enhances Their Contact with T Cells in Host Secondary Lymphoid Tissue: Implications for Abrogation of MHC-mismatched Liver Transplant Tolerance in Mice [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/absence-of-dap12-expression-by-donor-liver-derived-dendritic-cells-enhances-their-contact-with-t-cells-in-host-secondary-lymphoid-tissue-implications-for-abrogation-of-mhc-mismatched-liver-transplant/. Accessed December 10, 2024.« Back to 2022 American Transplant Congress