The Presence of HLA-E-Restricted, CMV-Specific CD8+ T Cells in the Blood of Lung Transplant Recipients Correlates with Chronic Allograft Rejection.

Lucy C Sullivan,Glen P Westall,Jacqueline M L Widjaja,Tom C Kotsimbos,Nicole A Mifsud,Andrew G Brooks,Thi H O Nguyen,Aislin C Meehan

doi:10.1371/journal.pone.0135972

Abstract

The human cytomegalovirus (CMV) immune evasion protein, UL40, shares an identical peptide sequence with that found in the leader sequence of many human leukocyte antigen (HLA)-C alleles and when complexed with HLA-E, can modulate NK cell functions via interactions with the CD94-NKG2 receptors. However the UL40-derived sequence can also be immunogenic, eliciting robust CD8+ T cell responses. In the setting of solid organ transplantation these T cells may not only be involved in antiviral immunity but also can potentially contribute to allograft rejection when the UL40 epitope is also present in allograft-encoded HLA. Here we assessed 15 bilateral lung transplant recipients for the presence of HLA-E-restricted UL40 specific T cells by tetramer staining of peripheral blood mononuclear cells (PBMC). UL40-specific T cells were observed in 7 patients post-transplant however the magnitude of the response varied significantly between patients. Moreover, unlike healthy CMV seropositive individuals, longitudinal analyses revealed that proportions of such T cells fluctuated markedly. Nine patients experienced low-grade acute cellular rejection, of which 6 also demonstrated UL40-specific T cells. Furthermore, the presence of UL40-specific CD8+ T cells in the blood was significantly associated with allograft dysfunction, which manifested as Bronchiolitis Obliterans Syndrome (BOS). Therefore, this study suggests that minor histocompatibility antigens presented by HLA-E can represent an additional risk factor following lung transplantation.

Highlights

The role of non-classical major histocompatibility (MHC) class I molecules such as human leukocyte antigen (HLA)-E in adaptive immunity are only just beginning to be understood
natural killer (NK) cell recognition of HLA-E expressed on healthy cells is acutely dependent on the presence of conserved peptides found in the leader sequence of MHC class Ia molecules [2,5,6]
As expected HLA-E tetramer complexed to either VMAPRTLIL or VMPARTLFL bound to a large population of CD8β- cells together with another distinct population of CD8β+ cells since CD94-NKG2 receptors are widely expressed on both NK cells and CD8+ T cells

Summary

Introduction

The role of non-classical major histocompatibility (MHC) class I molecules (class Ib) such as human leukocyte antigen (HLA)-E in adaptive immunity are only just beginning to be understood. NK cell recognition of HLA-E expressed on healthy cells is acutely dependent on the presence of conserved peptides found in the leader sequence of MHC class Ia molecules [2,5,6]. It has been hypothesised that the major function of HLA-E is to allow NK cells to broadly monitor the expression of diverse MHC-I molecules since the acquisition of these peptides by HLA-E and their subsequent transport to the cell surface is dependent on the integrity of antigen processing machinery [3]. Any loss of HLA-E/class I-derived peptide complexes that may occur as a result of transformation or viral infection can promote target cell lysis by CD94-NKG2A+ NK cells

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Results

Conclusion