Potential Beneficial Effects of Cytomegalovirus Infection after Transplantation

Abstract

Cytomegalovirus (CMV) infection can cause significant complications after transplantation, but recent emerging data suggest that CMV may paradoxically also exert beneficial effects in two specific allogeneic transplant settings. These potential benefits have been underappreciated and are therefore highlighted in this review. First, after allogeneic hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) using T-cell and natural killer (NK) cell-replete grafts, CMV reactivation is associated with protection from leukemic relapse. This association was not observed for other hematologic malignancies. This anti-leukemic effect might be mediated by CMV-driven expansion of donor-derived memory-like NKG2C⁺ NK and Vδ2^negγδ T-cells. Donor-derived NK cells probably recognize recipient leukemic blasts by engagement of NKG2C with HLA-E and/or by the lack of donor (self) HLA molecules. Vδ2^negγδ T cells probably recognize as yet unidentified antigens on leukemic blasts via their TCR. Second, immunological imprints of CMV infection, such as expanded numbers of Vδ2^negγδ T cells and terminally differentiated TCRαβ⁺ T cells, as well as enhanced NKG2C gene expression in peripheral blood of operationally tolerant liver transplant patients, suggest that CMV infection or reactivation may be associated with liver graft acceptance. Mechanistically, poor alloreactivity of CMV-induced terminally differentiated TCRαβ⁺ T cells and CMV-induced IFN-driven adaptive immune resistance mechanisms in liver grafts may be involved. In conclusion, direct associations indicate that CMV reactivation may protect against AML relapse after allogeneic HSCT, and indirect associations suggest that CMV infection may promote allograft acceptance after liver transplantation. The causative mechanisms need further investigations, but are probably related to the profound and sustained imprint of CMV infection on the immune system.

Keywords: cytomegalovirus infections; hematopoietic stem cell transplantation; leukemia; solid organ transplantation; tolerance.

Figure 1

Schematic overview of (potential) beneficial effects of cytomegalovirus (CMV) infection after transplantation. This schematic overview illustrates the (potential) beneficial effects exhibited by different CMV-induced immune cell subsets and intra-graft IFN-signaling pathways after transplantation. Compelling evidence exists for anti-leukemic effects of CMV-induced donor-derived memory-like natural killer (NK) cells after hematopoietic stem cell transplantation (HSCT) in acute myeloid leukemia (AML) patients, and two mechanisms have been described. One involves enhanced expression of the activating NK-receptor NKG2C, at the expense of the inhibitory NKG2A, interacting with HLA-E expressed by AML blasts. The other mechanism involves the “missing self” principle, as recipient tumor cells do not express donor HLA class I and are, therefore, a target for killing by donor-derived NK cells as a result of lack of inhibition via donor HLA class I-recognizing inhibitory killer cell immunoglobulin-like receptors. CMV-induced TCRδ2⁻ γδ T cells have also been associated with anti-leukemic effects after HSCT, probably via recognition of an as yet unknown ligand by their TCR. Evidence implicating CMV-specific TCR αβ T cells in preventing AML relapse after HSCT is lacking. In addition, CMV-induced immune cell subsets have been associated with graft acceptance and liver-transplant tolerance. Evidence merely consists of associations and no detailed mechanistic insights are available yet. Induction of terminally differentiated TCRαβ T cells with low alloreactivity by CMV infection in various types of solid organ transplantations may be involved in development of graft acceptance. CMV-induced circulating TCRδ2⁻ γδ T cells are associated with liver transplant tolerance, but probably not functionally involved. Overexpression of NKG2C in peripheral blood is associated with both CMV infection and graft acceptance after liver transplantation, but whether a causal exists between NKG2C⁺ NK cells and graft acceptance is unknown. Apart from CMV-induced immune cell subsets, intra-graft IFN-α, β, and γ production, which can be induced by CMV, has been associated with liver transplant tolerance by induction of PD-L1 expression in the graft, thereby counteracting the host immune response.