Signaling pathways involved in the T‐cell‐mediated immunity against Epstein‐Barr virus: Lessons from genetic diseases

Abstract

Primary immunodeficiencies (PIDs) provide researchers with unique models to understand in vivo immune responses in general and immunity to infections in particular. In humans, impaired immune control of Epstein-Barr virus (EBV) infection is associated with the occurrence of several different immunopathologic conditions; these include non-malignant and malignant B-cell lymphoproliferative disorders, hemophagocytic lymphohistiocytosis (HLH), a severe inflammatory condition, and a chronic acute EBV infection of T cells. Studies of PIDs associated with a predisposition to develop severe, chronic EBV infections have led to the identification of key components of immunity to EBV -notably the central role of T-cell expansion and its regulation in the pathophysiology of EBV-associated diseases. On one hand, the defective expansion of EBV-specific CD8 T cells results from mutations in genes involved in T-cell activation (such as RASGRP1, MAGT1, and ITK), DNA metabolism (CTPS1) or co-stimulatory pathways (CD70, CD27, and TNFSFR9 (also known as CD137/4-1BB)) leads to impaired elimination of proliferating EBV-infected B cells and the occurrence of lymphoma. On the other hand, protracted T-cell expansion and activation after the defective killing of EBV-infected B cells is caused by genetic defects in the components of the lytic granule exocytosis pathway or in the small adapter protein SH2D1A (also known as SAP), a key activator of T-and NK cell-cytotoxicity. In this setting, the persistence of EBV-infected cells results in HLH, a condition characterized by unleashed T-cell and macrophage activation. Moreover, genetic defects causing selective vulnerability to EBV infection have highlighted the role of co-receptor molecules (CD27, CD137, and SLAM-R) selectively involved in immune responses against infected B cells via specific T-B cell interactions. K E Y W O R D S B-cell lymphoproliferation, cell-cytotoxicity, Epstein-Barr virus, hemophagocytic lymphohistiocytosis, primary immunodeficiency, T-cell proliferation | IMMUNE RE S P ON S E S TO EBV INFEC TI ONEpstein-Barr virus (EBV, also known as human herpesvirus 4) is a gamma herpes virus that only infects primates (primarily humans). 1,2 It is an encapsidated, double-stranded DNA virus with more than 100 genes. It is pandemic, since the great majority of human beings (>90%) have been infected by EBV. The main cell target is B lymphocytes that express CD21 -the membrane receptor for EBV entry through its 350 kDa major envelope glycoprotein. In immunocompetent adolescents and adults, EBV infection causes infectious mononucleosis (IM). Immunologically speaking, IM is characterized by a This article is part of a series of reviews covering Signaling and Signal Diversification in Immune

Human genetic basis of fulminant viral hepatitis

“…This study was the first to investigate why only some HAV-infected individuals develop FVH. However, given the incidence of the disease, the allele frequency in the general population is too high to be compatible with the hypothesis of single-gene IEI, as previously reported in other severe viral diseases (Byun et al 2013;Ciancanelli et al 2015Ciancanelli et al , 2016Jong et al 2018a, b;Hernandez et al 2018Hernandez et al , 2019Jackson et al 2016;Tangye and Latour 2020;Zhang and Casanova 2015;Zhang et al 2018Zhang et al , 2019Lafaille et al 2012Lafaille et al , 2015Latour and Fischer 2019). In 2014, a second study was performed on a cohort of ten adult patients with acute liver injury or failure due to HAV.…”

“…Conversely, reports of rare multiplex and/or consanguineous families have suggested a possible contribution of inborn errors of immunity (IEI) (Durst et al 2001;Yalniz et al 2005;Yoshida et al 2017). Moreover, single-gene IEI have been found to underlie other severe, isolated viral infections, such as herpes simplex virus encephalitis, attenuated live measles and yellow fever vaccine diseases, Kaposi sarcoma, severe influenza pneumonitis, epidermodysplasia verruciformis, and fulminant EBV disease (Byun et al 2013;Ciancanelli et al 2015Ciancanelli et al , 2016Jong et al 2018a, b;Hernandez et al 2018Hernandez et al , 2019Jackson et al 2016;Tangye and Latour 2020;Zhang and Casanova 2015;Zhang et al 2018Zhang et al , 2019Lafaille et al 2012Lafaille et al , 2015Latour and Fischer 2019). These observations suggest that FVH may be caused by a liver IEI to viruses.…”

The Role of Dendritic Cells in Immune Control and Vaccination against γ-Herpesviruses

“…This becomes apparent under conditions of immune suppression by human immunodeficiency virus (HIV) co-infection, iatrogenic immune suppression after organ transplantation, or primary immunodeficiencies, which lead primarily to EBV associated lymphomas and KSHV associated lymphomas or Kaposi sarcoma. The lesions in the human immune system of patients with primary immunodeficiencies identify T lymphocytes as the main components of the immune control of the two γ-herpesviruses, cytotoxic CD8 + T and NK cells for EBV and IFN-γ producing T cells for KSHV [13][14][15]. In contrast to the protective function of cytokines against KSHV, cytokine production due to T cell hyperactivation during ill-controlled EBV infection can lead to immune pathologies, including the symptomatic primary EBV infection, called infectious mononucleosis (IM) and hemophagocytic lymphohistiocytosis (HLH) [4,16,17].…”

“…It is particularly connected to type II interferon (IFN-γ) induction in T and NK cells. Deficiencies in IFN-γ production in response to IL-12 production (mutations in IL-12p40, IL-12 receptor β1, IRF8, ISG15, and NEMO) and in IFN-γ detection (mutations in IFN-γ receptor 1 and 2, STAT1, IRF8, and CYBB) do not predispose for uncontrolled EBV pathology [14], but instead sensitize for mycobacterium associated pathologies [31]. In contrast, IFN-γ receptor 1 and STAT4 deficiencies lead to KSHV pathology [32,33].…”

“…In contrast to cDCs, pDCs are stimulated by EBV, but also primary immunodeficiencies that compromise their type I IFN production or sensing of this group of cytokines are not associated with EBV pathology [14]. These include mutations in IFN-α/β receptor, STAT1, IRF7, and TYK2 and predispose for α-herpesvirus, e.g., herpes simplex virus (HSV) and associated encephalitis [34].…”