Presentation of an Immunodominant Immediate-Early CD8+ T Cell Epitope Resists Human Cytomegalovirus Immunoevasion

Stefanie Ameres,Michael Neuenhahn,Josef Mautner,Fabian Schlott,Dirk H Busch,Bodo Plachter,Andreas Moosmann

doi:10.1371/journal.ppat.1003383

Abstract

Control of human cytomegalovirus (HCMV) depends on CD8+ T cell responses that are shaped by an individual's repertoire of MHC molecules. MHC class I presentation is modulated by a set of HCMV-encoded proteins. Here we show that HCMV immunoevasins differentially impair T cell recognition of epitopes from the same viral antigen, immediate-early 1 (IE-1), that are presented by different MHC class I allotypes. In the presence of immunoevasins, HLA-A- and HLA-B-restricted T cell clones were ineffective, but HLA-C*0702-restricted T cell clones recognized and killed infected cells. Resistance of HLA-C*0702 to viral immunoevasins US2 and US11 was mediated by the alpha3 domain and C-terminal region of the HLA heavy chain. In healthy donors, HLA-C*0702-restricted T cells dominated the T cell response to IE-1. The same HLA-C allotype specifically protected infected cells from attack by NK cells that expressed a corresponding HLA-C-specific KIR. Thus, allotype-specific viral immunoevasion allows HCMV to escape control by NK cells and HLA-A- and HLA-B-restricted T cells, while the virus becomes selectively vulnerable to an immunodominant population of HLA-C-restricted T cells. Our work identifies a T cell population that may be of particular efficiency in HCMV-specific immunotherapy.

Highlights

Human cytomegalovirus (HCMV) latently infects a majority of humans for their lifetime
Infected cells are recognized because they display MHC class I molecules that have bound a peptide derived from a viral protein
We show here for one viral antigen, immediate-early 1 (IE-1), that viral interference with T cell recognition strongly depends on the identity of the HLA molecule: HLA-A- and HLA-B-restricted T cells are fully inhibited, but HLA-C-restricted T cells that target an epitope from the same antigen recognize and kill infected cells with high efficiency

Summary

Introduction

Human cytomegalovirus (HCMV) latently infects a majority of humans for their lifetime. But can cause severe morbidity and mortality in immunocompromised patients and after congenital or neonatal infection [1]. In particular the virus-specific CD8+ T cell response, is of vital importance for controlling the virus [2]. After allogeneic stem cell transplantation, virus-specific CD8+ T cells are associated with protection from HCMV disease [3], and specific immunity in patients can be reconstituted by adoptive transfer of virus-specific CD8+ T cells [4,5,6]. Congenital HCMV infection has a higher frequency of causing harm when a non-immune mother acquires the virus for the first time during pregnancy [7], suggesting that pre-established maternal immunity is partially protective. Neither HCMV-specific adoptive T cell therapy nor HCMV-specific vaccines [8,9] have moved beyond the stage of clinical testing

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