Revisiting the Tissue Microenvironment of Infectious Mononucleosis: Identification of EBV Infection in T Cells and Deep Characterization of Immune Profiles.

Mário Henrique M Barros,Priscilla Segges,Gabriela Vera-Lozada,Rocio Hassan,Gerald Niedobitek

doi:10.3389/fimmu.2019.00146

Abstract

To aid understanding of primary EBV infection, we have performed an in depth analysis of EBV-infected cells and of local immune cells in tonsils from infectious mononucleosis (IM) patients. We show that EBV is present in approximately 50% of B-cells showing heterogeneous patterns of latent viral gene expression probably reflecting different stages of infection. While the vast majority of EBV+ cells are B-cells, around 9% express T-cell antigens, with a predominance of CD8+ over CD4+ cells. PD-L1 was expressed by a median of 14% of EBV+ cells. The numbers of EBER+PD-L1+ cells were directly correlated with the numbers of EBER+CD3+ and EBER+CD8+ cells suggesting a possible role for PD-L1 in EBV infection of T-cells. The microenvironment of IM tonsils was characterized by a predominance of M1-polarized macrophages over M2-polarized cells. However, at the T-cell level, a heterogeneous picture emerged with numerous Th1/cytotoxic cells accompanied and sometimes outnumbered by Th2/regulatory T-cells. Further, we observed a direct correlation between the numbers of Th2-like cells and EBV– B-cells. Also, a prevalence of cytotoxic T-cells over Th2-like cells was associated with an increased viral load. These observations point to contribution of B- and Th2-like cells to the control of primary EBV infection. 35% of CD8+ cells were differentiated CD8+TBET+ cells, frequently detected in post-capillary venules. An inverse correlation was observed between the numbers of CD8+TBET+ cells and viral load suggesting a pivotal role for these cells in the control of primary EBV infection. Our results provide the basis for a better understanding of immune reactions in EBV-associated tumors.

Highlights

Epstein-Barr virus (EBV) infects more than 90% of adults worldwide and persists in memory B lymphocytes as a life-long asymptomatic infection [1]
In contrast to the vast amount of knowledge derived from studies focusing on EBV-infected cells, immune cells and antibody response in peripheral blood [1, 3, 6,7,8,9,10,11], only few studies have focused on the characteristics of EBV infection and the tissue microenvironment response at the main anatomical site of primary virus infection [6, 12,13,14,15] and detailed information as to what happens in the tonsils of these patients is still wanting
The majority of these cells were predominantly found in the interfollicular regions, small numbers of EBV-encoded nuclear RNAs (EBERs)+ cells were observed in the germinal centers and within the tonsillar crypt epithelium

Summary

Introduction

Epstein-Barr virus (EBV) infects more than 90% of adults worldwide and persists in memory B lymphocytes as a life-long asymptomatic infection [1]. In IM, characteristically, there is a florid T cell response mainly consisting of activated CD8+ cytotoxic T cells specific for lytic, and to a lesser extent, latent viral antigens expressed in EBV-infected B-cells [1, 3]. Knowledge about this response, with its particular antigenic hierarchy and dynamics has been accumulating during the last decades [4, 5]. Quantity and composition of the local immune cell response, the relation between the magnitude of EBV-infection and the local immune response signature, and the extent to which the immune response observed in the peripheral blood is reflected in the tissue microenvironment remain unexplored

Methods

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Conclusion