Killing of myeloid APCs via HLA class I, CD2 and CD226 defines a novel mechanism of suppression by human Tr1 cells

Chiara F Magnani,Marco Andreani,Giada Alberigo,Maria Grazia Roncarolo,Rosa Bacchetta,Silvia Gregori,Giorgia Serafini

doi:10.1002/eji.201041120

Abstract

IL-10-producing CD4+ type 1 regulatory T (Tr1) cells, defined based on their ability to produce high levels of IL-10 in the absence of IL-4, are major players in the induction and maintenance of peripheral tolerance. Tr1 cells inhibit T-cell responses mainly via cytokine-dependent mechanisms. The cellular and molecular mechanisms underlying the suppression of APC by Tr1 cells are still not completely elucidated. Here, we defined that Tr1 cells specifically lyse myeloid APC through a granzyme B (GZB)- and perforin (PRF)-dependent mechanism that requires HLA class I recognition, CD54/lymphocyte function-associated antigen (LFA)-1 adhesion, and activation via killer cell Ig-like receptors (KIRs) and CD2. Notably, interaction between CD226 on Tr1 cells and their ligands on myeloid cells, leading to Tr1-cell activation, is necessary for defining Tr1-cell target specificity. We also showed that high frequency of GZB-expressing CD4+ T cells is detected in tolerant patients and correlates with elevated occurrence of IL-10-producing CD4+ T cells. In conclusion, the modulatory activities of Tr1 cells are not only due to suppressive cytokines but also to specific cell-to-cell interactions that lead to selective killing of myeloid cells and possibly bystander suppression.

Highlights

CD41 type 1 regulatory T (Tr1) cells are adaptive IL-10-producing Tregs fundamental in controlling immune responses and in inducing peripheral tolerance both in humans and mice [1, 2].The first indication that type 1 regulatory T Á b-thal (Tr1) cells mediate peripheral tolerance in vivo came from SCID patients who developed long-term tolerance to stem cell allograft [1]
IL-10-producing Tr1 cells represent 10–15% of the polarized population, granzyme B (GZB) expression is not restricted to this population of cells (Fig. 1B)
We demonstrate that human Tr1 cells, in vitro generated and ex vivo isolated, express and release high levels of GZB, and lyse target cells of myeloid origin, but not T and B lymphocytes

Summary

Introduction

CD41 type 1 regulatory T (Tr1) cells are adaptive IL-10-producing Tregs fundamental in controlling immune responses and in inducing peripheral tolerance both in humans and mice [1, 2]. The first indication that Tr1 cells mediate peripheral tolerance in vivo came from SCID patients who developed long-term tolerance to stem cell allograft [1]. Tr1 cells are Ag-specific, hypo-responsive, and suppress effector T cells mainly by the release of IL-10 and TGF-b [2]. It has been hypothesized that a cell-contact-dependent mechanism cooperates with the release of immunosuppressive cytokines in inhibiting immune responses by Tr1 cells, since the addition of neutralizing antibodies against IL-10R and TGF-b did not completely revert suppression mediated by Tr1 cells [5]

Methods

Results

Conclusion