A Diverse Repertoire of CD4 T Cells Targets the Immediate-Early 1 Protein of Human Cytomegalovirus.

Stefanie Ameres,Xiaoling Liang,Josef Mautner,Andreas Moosmann,Martina Wiesner

doi:10.3389/fimmu.2015.00598

Abstract

T-cell responses to the immediate-early 1 (IE-1) protein of human cytomegalovirus (HCMV) are associated with protection from viral disease. Thus, IE-1 is a promising target for immunotherapy. CD8 T-cell responses to IE-1 are generally strong. In contrast, CD4 T-cell responses to IE-1 were described to be comparatively infrequent or undetectable in HCMV carriers, and information on their target epitopes and their function has been limited. To analyze the repertoire of IE-1-specific CD4 T cells, we expanded them from healthy donors with autologous IE-1-expressing mini-Epstein–Barr virus-transformed B-cell lines and established IE-1-specific CD4 T-cell clones. Clones from seven out of seven HCMV-positive donors recognized endogenously processed IE-1 epitopes restricted through HLA-DR, DQ, or DP. Three to seven IE-1 epitopes were recognized per donor. Cumulatively, about 27 different HLA/peptide class II complexes were recognized by 117 IE-1-specific clones. Our results suggest that a highly diversified repertoire of IE-1-specific CD4 T cells targeting multiple epitopes is usually present in healthy HCMV carriers. Therefore, multiepitope approaches to immunomonitoring and immunotherapy will make optimal use of this potentially important class of HCMV-specific effector cells.

Highlights

Persistent infection with human cytomegalovirus (HCMV) is widespread in healthy humans [1]
For each of the seven donors, the enriched CD4+ T cells recognized a subset of immediate-early 1 (IE-1) peptide subpools, often others than were recognized by CD8+ (CD4-depleted) T cells from the same donor, and often ones that elicited no detectable reactivity from PBMC ex vivo (Figure 1B)
We show that IE-1-specific CD4 T cells can regularly be isolated from HCMV-positive donors of various HLA backgrounds

Summary

Introduction

Persistent infection with human cytomegalovirus (HCMV) is widespread in healthy humans [1]. Control of viral replication and disease is believed to critically depend on HCMV-specific T cells [2]. In transplanted patients whose virus-specific T-cell response is impaired, HCMV can cause severe and potentially fatal disease [3]. Reconstitution of HCMVspecific T cells by adoptive transfer is associated with control of HCMV infection and disease, in particular in the situation after allogeneic stem cell transplantation where a compatible donor of HCMV-specific T cells is available [5]. Some approaches to adoptive T-cell transfer primarily aim at reconstituting HCMV-specific CD8 T cells [6, 7], it appears that HCMV-specific CD4 T cells play an important role in therapeutic success [5, 8]

Methods

Results

Conclusion