Interferon-γ converts human microvascular pericytes into negative regulators of alloimmunity through induction of indoleamine 2,3-dioxygenase 1

JCI Insight. 2018 Mar 8;3(5):e97881. doi: 10.1172/jci.insight.97881.

Abstract

Early acute rejection of human allografts is mediated by circulating alloreactive host effector memory T cells (TEM). TEM infiltration typically occurs across graft postcapillary venules and involves sequential interactions with graft-derived endothelial cells (ECs) and pericytes (PCs). While the role of ECs in allograft rejection has been extensively studied, contributions of PCs to this process are largely unknown. This study aimed to characterize the effects and mechanisms of interactions between human PCs and allogeneic TEM. We report that unstimulated PCs, like ECs, can directly present alloantigen to TEM, but while IFN-γ-activated ECs (γ-ECs) show increased ability to stimulate alloreactive T cells, IFN-γ-activated PCs (γ-PCs) instead suppress TEM proliferation but not cytokine production or signaling. RNA sequencing analysis of PCs, γ-PCs, ECs, and γ-ECs reveal induction of indoleamine 2,3-dioxygenase 1 (IDO1) in γ-PCs to significantly higher levels than in γ-ECs that correlates with tryptophan depletion in vitro. Consistently, shRNA knockdown of IDO1 markedly reduces γ-PC-mediated immunoregulatory effects. Furthermore, human PCs express IDO1 in a skin allograft rejection humanized mouse model and in human renal allografts with acute T cell-mediated rejection. We conclude that immunosuppressive properties of human PCs are not intrinsic but instead result from IFN-γ-induced IDO1-mediated tryptophan depletion.

Keywords: Adaptive immunity; Pericytes; T cells; Transplantation; Vascular Biology.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allografts / blood supply
  • Allografts / cytology
  • Allografts / immunology*
  • Animals
  • Antigen Presentation / immunology
  • Cell Communication / immunology
  • Cells, Cultured
  • Disease Models, Animal
  • Endothelial Cells / immunology
  • Endothelium, Vascular / cytology
  • Female
  • Graft Rejection / immunology*
  • Healthy Volunteers
  • Human Umbilical Vein Endothelial Cells
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / genetics
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / immunology
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism*
  • Interferon-gamma / immunology
  • Interferon-gamma / metabolism*
  • Isoantigens / immunology
  • Mice, SCID
  • Microvessels / cytology
  • Microvessels / immunology
  • Pericytes / immunology*
  • Pericytes / metabolism
  • Primary Cell Culture
  • RNA, Small Interfering / metabolism
  • Skin / blood supply
  • Skin / cytology
  • Skin / immunology
  • Skin Transplantation / adverse effects
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / metabolism
  • Transplantation Chimera
  • Transplantation, Homologous / adverse effects
  • Tryptophan / metabolism

Substances

  • IDO1 protein, human
  • IFNG protein, human
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Isoantigens
  • RNA, Small Interfering
  • Interferon-gamma
  • Tryptophan