Donor plasmacytoid dendritic cells modulate effector and regulatory T cell responses in mouse spontaneous liver transplant tolerance

Am J Transplant. 2021 Jun;21(6):2040-2055. doi: 10.1111/ajt.16412. Epub 2021 Jan 4.

Abstract

We assessed the role of donor liver non-conventional plasmacytoid dendritic cells (pDCs) in spontaneous liver transplant tolerance in a fully MHC-mismatched (C57BL/6 (H2b ) to C3H (H2k )) mouse model. Compared with spleen pDCs, liver pDCs expressed higher levels of DNAX-activating protein of 12 kDa and its co-receptor, triggering receptor expressed by myeloid cells 2, and higher ratios of programed death ligand-1 (PD-L1):costimulatory CD80/CD86 in the steady state and after Toll-like receptor 9 ligation. Moreover, liver pDCs potently suppressed allogeneic CD4+ and CD8+ T cell proliferative responses. Survival of pDC-depleted livers was much poorer (median survival time: 25 days) than that of either untreated donor livers or pDC-depleted syngeneic donor livers that survived indefinitely. Numbers of forkhead box p3 (FoxP3)+ regulatory T cells in grafts and mesenteric lymph nodes of mice given pDC-depleted allogeneic livers were reduced significantly compared with those in recipients of untreated livers. Graft-infiltrating CD8+ T cells with an exhausted phenotype (programed cell death protein 1+ , T cell immunoglobulin and mucin domain-containing protein 3+ ) were also reduced in recipients of pDC-depleted livers. PD1-PD-L1 pathway blockade reversed the reduction in exhausted T cells. These novel observations link immunoregulatory functions of liver interstitial pDCs, alloreactive T cell exhaustion, and spontaneous liver transplant tolerance.

Keywords: basic (laboratory) research/science; cell death: exhaustion; cellular biology; dendritic cell; immune regulation; immunobiology; liver biology; liver transplantation/hepatology; tolerance: experimental.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • CD8-Positive T-Lymphocytes
  • Dendritic Cells
  • Humans
  • Liver Transplantation*
  • Living Donors
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • T-Lymphocytes, Regulatory*