Tr1 Cells as a Key Regulator for Maintaining Immune Homeostasis in Transplantation

Abstract

The immune system is composed of effectors and regulators. Type 1 regulatory T (Tr1) cells are classified as a distinct subset of T cells, and they secret high levels of IL-10 but lack the expression of the forkhead box P3 (Foxp3). Tr1 cells act as key regulators in the immune network, and play a central role in maintaining immune homeostasis. The regulatory capacity of Tr1 cells depends on many mechanisms, including secretion of suppressive cytokines, cell-cell contacts, cytotoxicity and metabolic regulation. A breakdown of Tr1-cell-mediated tolerance is closely linked with the pathogenesis of various diseases. Based on this observation, Tr1-cell therapy has emerged as a successful treatment option for a number of human diseases. In this review, we describe an overview of Tr1 cell identification, functions and related molecular mechanisms. We also discuss the current protocols to induce/expand Tr1 cells in vitro for clinical application, and summarize the recent progress of Tr1 cells in transplantation.

Keywords: biomarkers; clinical trials; regulatory functions; transcription factor; transplantation; type 1 regulatory T cells.

Figure 1

General characteristics of Tr1 cells. The biomarkers for Tr1 cells include surface molecules, secreted cytokines and transcription factors.

Figure 2

Multiple suppressive mechanisms of Tr1 cells in immune responses. The mechanisms of Tr1 cells to inhibit effector cells include: (1) Tr1 cells exert their suppressive function primarily via the secretion of IL-10 and TGF-β. (2) Tr1 cells contact and suppress other effector cells through inhibitory receptors, including CTLA-4 and PD-1. (3) Tr1 cells selectively kill myeloid APCs via secretion of Granzyme B and perforin to inhibit effector T cells. (4) CD39 and CD73 on Tr1 cells produce adenosine which increase intracellular cAMP levels and disrupts effector T cell metabolism.

Figure 3

Transcriptional regulation of signaling pathways during Tr1 cell induction. Cytokines, cytokine receptors and transcription factors establish a signaling transduction network to induce Tr1 cells in vitro and in vivo. IL-27 is a key cytokine in these pathways. IL-27 activates c-Maf and AhR. IL-27 along with TCR stimulation also induces high levels of Egr-2 which drives Blimp-1 expression. Conversely, TGF-β signaling antagonizes Blimp-1 by inducing AhR and c-Maf. c-Maf, AhR and Egr-2-Blimp-1 axis promote IL-10 and IL-21 secretion. The autocrine IL-10 and IL-21 maintain Tr1 cell stability via p38 MAPK and STAT3 respectively. Eomes is another key transcription factor. Eomes is dependent on IL-27, and interacts Blimp-1 to activate IL-10 expression. IRF1 and BATF which induced by TCR activation and IL-27 prepare the chromatin landscape for induction of the Tr1 gene network. IL-6 and other STAT3 activating cytokines might utilize the same transcriptional factors to generate Tr1 cells.