Direct and Indirect Effects of Cytomegalovirus-Induced γδ T Cells after Kidney Transplantation

Abstract

Despite effective anti-viral therapies, cytomegalovirus (CMV) is still associated with direct (CMV disease) and indirect effects (rejection and poor graft survival) in kidney transplant recipients. Recently, an unconventional T cell population (collectively designated as Vδ2(neg) γδ T cells) has been characterized during the anti-CMV immune response in all solid-organ and bone-marrow transplant recipients, neonates, and healthy people. These CMV-induced Vδ2(neg) γδ T cells undergo a dramatic and stable expansion after CMV infection, in a conventional "adaptive" manner. Similarly, as CMV-specific CD8+ αβ T cells, they exhibit an effector/memory TEMRA phenotype and cytotoxic effector functions. Activation of Vδ2(neg) γδ T cells by CMV-infected cells involves the γδ T cell receptor (TCR) and still ill-defined co-stimulatory molecules such as LFA-1. A multiple of Vδ2(neg) γδ TCR ligands are apparently recognized on CMV-infected cells, the first one identified being the major histocompatibility complex-related molecule endothelial protein C receptor. A singularity of CMV-induced Vδ2(neg) γδ T cells is to acquire CD16 expression and to exert an antibody-dependent cell-mediated inhibition on CMV replication, which is controlled by a specific cytokine microenvironment. Beyond the well-demonstrated direct anti-CMV effect of Vδ2(neg) γδ T cells, unexpected indirect effects of these cells have been also observed in the context of kidney transplantation. CMV-induced Vδ2(neg) γδ T cells have been involved in surveillance of malignancy subsequent to long-term immunosuppression. Moreover, CMV-induced CD16+ γδ T cells are cell effectors of antibody-mediated rejection of kidney transplants, and represent a new physiopathological contribution to the well-known association between CMV infection and poor graft survival. All these basic and clinical studies paved the road to the development of a future γδ T cell-based immunotherapy. In the meantime, γδ T cell monitoring should prove a valuable immunological biomarker in the management of CMV infection.

Keywords: antibody-mediated rejection; cancer; cytomegalovirus; gamma-delta T cells; lymphocytes; renal transplantation.

Figure 1

Phenotype of CMV-induced Vδ2^negγδ T cells and CMV-specific CD8+ αβ T cells. Both subsets exhibit a similar effector/memory TEMRA phenotype.

Figure 2

Composition of the CD16+ lymphocyte compartment in CMV-seropositive (CMV+) and CMV-seronegative (CMV−) people. CMV infection doubles the number of circulating CD16+ lymphocytes, through this expansion of CD16+ Vδ2^negγδ T cells.

Figure 3

In vitro and in vivo direct and indirect effects of CMV-induced Vδ2^negγδ T cells. (A) In culture with CMV-infected cells, Vδ2^neg γδ T cell lines or clones coming from CMV-infected solid-organ transplant recipients produce large amounts of TNF-α and/or interferon-γ, and exert a strong cytotoxicity against CMV-infected cells. Vδ2^neg γδ T cell reactivity requires EPCR expression and co-stimulatory molecules, which are over expressed in CMV-infected cells, as LFA-3 (CD2 ligand) and ICAM-1 (LFA-1 ligand). (B) In the absence of TCR stimulation, CD16+ Vδ2^negγδ T cells produce interferon-γ and inhibit CMV replication when activate by IgG-opsonized free CMV, in presence of IL-12 and interferon-α, two cytokines produced by monocytes/macrophages and dendritic cells during CMV infection. (C) CMV-induced Vδ2^neg γδ T cells have a TCR-dependent cross-reactivity against CMV-infected cells and tumor cells. (D) CMV-induced CD16+ Vδ2^negγδ T cells are able to perform antibody-dependent cell-mediated cytotoxicity (ADCC) against endothelial cells (EC) coated with donor-specific antibody (DSA). Within the grafts, γδ T cells are retrieved in close contact with endothelial cells in the peritubular capillaritis and glomerulitis associated with acute antibody-mediated rejection, only in CMV-experienced patients.