Cytomegalovirus-Infected Human Endothelial Cells Can Stimulate Allogeneic CD4+ Memory T Cells by Releasing Antigenic Exosomes

Abstract

Human CMV infection is controlled by T cell-mediated immunity and in immunosuppressed transplant patients it is associated with acute allograft rejection as well as chronic allograft vasculopathy. CMV infects endothelial cells (EC) and it is thought that CMV-specific host immune responses to infected allograft EC contribute to rejection. In vitro, CD4+ T cells from CMV-positive donors (but not CMV-negative donors) are readily activated by CMV-infected allogeneic EC, although it is unclear how allogeneic CMV-infected EC activate self-class II MHC-restricted memory CD4+ T cells. In this study, we confirm that purified CD4+ T cells from CMV+ donors are activated by allogeneic CMV-infected EC, but find that the response is dependent upon copurified APC expressing class II MHC that are autologous to the T cells. The transfer of CMV Ags from infected EC to APC can be mediated by EC-derived exosome-like particles. These results provide a mechanism by which CMV can exacerbate allograft rejection and suggest a novel function of EC-derived exosomes that could contribute in a more general manner to immune surveillance.

Extracellular vesicles: novel vehicles in herpesvirus infection

“…HCMV infection is always associated with acute allograft ejection and chronic allograft vasculopathy in transplant patients whose immune system is suppressed. By stimulating endothelial cells (ECs) to release antigenic exosomes, HCMV exacerbates allograft rejection in response to the allogeneic CD4 + memory T cell-mediated immunity (Walker et al, 2009), revealing a novel manner for EC-derived exosomes to evade immune surveillance. In addition, because ESCRT machinery is important for incorporating the viral cargo into MVBs, HCMV is reported to undergo maturation independent of ESCRT components, different from HSV-1 (Fraile-Ramos et al, 2007).…”

Cell-Cell Communication Via Extracellular Membrane Vesicles and Its Role in the Immune Response

“…Notably, exosomes derived from macrophages infected with an intracellular pathogen, such as Mycobacterium tuberculosis or Mycobacterium bovis, shed exosomes that are transmitted to distant DCs, leading to presentation of pathogenspecific antigens to CD4 + T cells and DC maturation. Similarly, exosomes derived from endothelial cells infected with cytomegalovirus (CMV) convey CMV-specific antigens to DCs to activate CD4 + T cells (Giri and Schorey, 2008;Walker et al, 2009).…”

Modification of the HCMV-specific IFN-γ release test (QuantiFERON-CMV) and a novel proposal for its application

“…The internalization of exogenous Ag into dendritic cells was suggested as one explanation of this overlap ; for example, dense bodies containing full HCMV proteins are secreted by infected cells and internalized by antigen -presenting cells resulting in the transport of exogenous Ag into the endogenous pathway 31) . Non -infectious enveloped particles secreted by infected endothelial cells appear to have a similar function 32) . In this study, we tested IE -1 and pp65 proteins as exogenous Ag and UV -inactivated HCMV particles as endogenous Ag.…”