The cellular and molecular mechanisms of immuno-suppression by human type 1 regulatory T cells

Abstract

The immuno-regulatory mechanisms of IL-10-producing type 1 regulatory T (Tr1) cells have been widely studied over the years. However, several recent discoveries have shed new light on the cellular and molecular mechanisms that human Tr1 cells use to control immune responses and induce tolerance. In this review we outline the well known and newly discovered regulatory properties of human Tr1 cells and provide an in-depth comparison of the known suppressor mechanisms of Tr1 cells with FOXP3(+) T(reg). We also highlight the role that Tr1 cells play in promoting and maintaining tolerance in autoimmunity, allergy, and transplantation.

Keywords: FOXP3+ Treg; IL-10; Tr1 cells; immunotolerance.

Figure 1

Mechanisms of suppression mediated by Tr1 cells. (A) Tr1 cells upon Ag-specific activation secrete IL-10 and TGF-β that directly inhibit the function of effector T cells and indirectly modulate APC, which in turn limit effector T cell proliferation and cytokine production. IL-10 produced by Tr1 cells up-regulates the expression of tolerogenic molecules (ILT3, ILT4, and HLA-G) on APC and their ability to produce IL-10, and become regulatory APC able to promote de novo induction of Tr1 cells. (B) CTLA-4 and PD-1 on Tr1 cells down-regulate or prevent the up-regulation of MHC class II and co-stimulatory molecules on APC upon interaction with their ligand, which limits effector T cell activation. (C) Catalytic inactivation of extracellular ATP by the ectoenzymes CD39 and CD73 represents an anti-inflammatory mechanism used by Tr1 cells to prevent effector T cell proliferation and cytokine production. (D) IL-10 produced by Tr1 cells upon activation promotes autocrine granzyme-B (GZ-B) that in association with perforin (PRF) allows an Ag-non-specific Tr1-mediated killing of myeloid APC. Myeloid-specific killing by Tr1 cells requires HLA class I activation and the expression of CD54, CD58, CD112, and CD155 on myeloid cells.