Cytomegalovirus-responsive γδ T cells: novel effector cells in antibody-mediated kidney allograft microcirculation lesions.

Thomas Bachelet,Xavier Sicard,Sébastien Lepreux,Jean-Luc Taupin,Jean-François Moreau,Claire Rigothier,Pierre Merville,Lionel Couzi,Julie Déchanet-Merville,Vincent Pitard

doi:10.1681/asn.2013101052

Abstract

Human cytomegalovirus infection in transplant recipients has been associated with adverse renal allograft outcome and with a large γδ T-cell response, but whether both mechanisms are connected is unknown. We previously showed that most expanded circulating cytomegalovirus-responsive γδ T cells express the Fcγ-receptor CD16, suggesting that γδ T cells may participate in allograft lesions mediated by donor-specific antibodies through antibody-dependent cellular cytotoxicity. Here, we show that cytomegalovirus-specific CD16(pos) γδ T cells can perform antibody-dependent cellular cytotoxicity against stromal cells coated with donor-specific antibodies in vitro. In vivo, graft-infiltrating γδ T cells localized in close contact with endothelial cells only in patients who experienced cytomegalovirus infection and were more frequent within peritubular capillaries and glomeruli from antibody-mediated acute rejections than within those from T cell-mediated acute rejections. Finally, a persistently increased percentage of circulating cytomegalovirus-induced γδ T cells correlated inversely with the 1-year eGFR only in kidney recipients with donor-specific antibodies. Collectively, these data support the conclusion that cytomegalovirus-induced γδ T cells are involved in, and may serve as a clinical biomarker of, antibody-mediated lesions of kidney transplants. Moreover, these findings offer a new physiopathologic link between cytomegalovirus infection and allograft dysfunction in recipients with donor-specific antibodies.

Highlights

In kidney transplant recipients (KTRs), the importance of the recipient’s humoral response against the allograft has been recognized to play a key role in immunologic injuries contributing to graft deterioration.[1,2,3,4,5,6] From an immunologic point of view, donor-specific antibody (DSA)–mediated lesions are considered to rely on complement-fixing DSA-mediated lysis, direct DSA-mediated apoptosis, or antibody-dependent cellmediated cytotoxicity (ADCC) by natural killer (NK) cells
Model of KTR DSA Binding to Endothelial and Fibroblastic Cells To assess the potential allocytotoxic effect of CMV-induced gd T cells in the presence of DSA, we used allogeneic stromal cell lines recognized by DSA
We assessed the ability of sera from eight KTRs with DSA and from two nonsensitized KTRs (S1 and S2) to bind three allogeneic HLA-typed “stromal” cells lines: an endothelial cell line (IVEC), primary foreskin fibroblasts (FSF), and MRC5

Summary

Introduction

In kidney transplant recipients (KTRs), the importance of the recipient’s humoral response against the allograft has been recognized to play a key role in immunologic injuries contributing to graft deterioration.[1,2,3,4,5,6] From an immunologic point of view, donor-specific antibody (DSA)–mediated lesions are considered to rely on complement-fixing DSA-mediated lysis, direct DSA-mediated apoptosis, or antibody-dependent cellmediated cytotoxicity (ADCC) by natural killer (NK) cells. Beside NK cells, and unlike conventional ab T cells, gd T cells can express CD16 at high levels, enabling them to efficiently mediate ADCC.[19] In human transplantation, gd T lymphocytes have been strongly linked to cytomegalovirus (CMV) infection, itself associated with rejection.[20,21,22] A specific and persistent expansion of a gd T-cell subset normally located in the epithelia (called Vd2neg gd T cells and mainly composed of Vd1 and Vd3 T cells) is observed in peripheral blood during CMV infection in all solid-organ transplantations.[23,24,25,26] From our experience, CMV is the only clinical cause of Vd2neg gd T-cell expansion in KTR This tight association between CMV infection and gd T-cell expansion has been confirmed in many other pathophysiologic contexts.[27,28,29,30,31] In vitro, clones of Vd2neg gd T cells display T-cell receptor (TCR)–dependent cytotoxicity against both CMV-infected cells and carcinoma cells.[32] their expansion in kidney transplant recipients correlates with both reduced cancer risk[33] and resolution of CMV infection, suggestive of their antiviral function.[34]. The latter are able to produce high levels of IFN-g when recognizing IgG-

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Results