γδ T Cell-Mediated Immunity to Cytomegalovirus Infection

Abstract

γδ T lymphocytes are unconventional immune cells, which have both innate- and adaptive-like features allowing them to respond to a wide spectrum of pathogens. For many years, we and others have reported on the role of these cells in the immune response to human cytomegalovirus in transplant patients, pregnant women, neonates, immunodeficient children, and healthy people. Indeed, and as described for CD8⁺ T cells, CMV infection leaves a specific imprint on the γδ T cell compartment: (i) driving a long-lasting expansion of oligoclonal γδ T cells in the blood of seropositive individuals, (ii) inducing their differentiation into effector/memory cells expressing a T_EMRA phenotype, and (iii) enhancing their antiviral effector functions (i.e., cytotoxicity and IFNγ production). Recently, two studies using murine CMV (MCMV) have corroborated and extended these observations. In particular, they have illustrated the ability of adoptively transferred MCMV-induced γδ T cells to protect immune-deficient mice against virus-induced death. In vivo, expansion of γδ T cells is associated with the clearance of CMV infection as well as with reduced cancer occurrence or leukemia relapse risk in kidney transplant patients and allogeneic stem cell recipients, respectively. Taken together, all these studies show that γδ T cells are important immune effectors against CMV and cancer, which are life-threatening diseases affecting transplant recipients. The ability of CMV-induced γδ T cells to act independently of other immune cells opens the door to the development of novel cellular immunotherapies that could be particularly beneficial for immunocompromised transplant recipients.

Keywords: antiviral immunity; bone marrow and organ transplantation; cytomegalovirus; memory T cells; γδ T cells.

Figure 1

Schematic representation of the primary and secondary response to CMV. Early during primary CMV infection, phagocytes and DCs are activated through TLRs and nucleic acid sensors by viral products and secrete pro-inflammatory cytokines (IFNαβ, IL-12, and IL-18) that induce NK cell and γδ T cell activation. Recognition of the protein m157 (C57BL/6 mouse) and HLA-E (human) or stress-induced ligands expressed by infected cells also stimulates NK cells and γδ T cells, respectively. This leads to the expansion of Ly49H⁺ (mouse) or NKG2C⁺ (human) NK cells and T_EM (mouse) or CD16⁺ T_EMRA (human) γδ T cells that persist over the long term. Activation of DCs leads to their maturation and migration to lymph nodes. Cross-presentation of viral peptides to naïve CD8⁺ αβ T cells induces their differentiation into T_EM or T_EMRA, expansion and acquisition of effector functions. Activated NK cells and αβ and γδ T cells can lyse and eliminate CMV-infected cells or control viral replication through secretion of anti-viral cytokines (e.g., IFNγ, TNFα). Despite the establishment of this immune response, CMV persists in its host. During viral reactivation episodes, CMV-induced immune cells react quickly to the presence of virions through the recognition of m157/HLA-E, stress antigens, or viral peptides. In addition, IFNγ secretion by CMV-elicited γδ T cells can be induced by CD16 interaction with Ig-opsonized viruses. The following color code has been used to distinguish mouse and human molecules or phenotypes: red color-mouse, blue color-human. Ag, antigen; CMV, cytomegalovirus; DC, dendritic cell; IFN, interferon, Ig, immunoglobulin; IL, interleukin; Mϕ, macrophage; NK, natural killer cell; T_EM, effector memory T cell; T_EMRA, CD45RA⁺ effector memory T cell; TLR, toll-like receptor.

Figure 2

Phenotypes of long-term cytomegalovirus (CMV)-induced NK, CD8⁺ αβ, and γδ T cells in humans and C57BL/6 mice. The main phenotypic and functional features of human (left panel) and mouse (right panel) CMV-induced NK and γδ T cells and CMV-specific CD8⁺ αβ T cells are listed. The surface markers commonly used to identify each population are emphasized in bold. As depicted, human and murine CMV-induced γδ T cells express an effector/memory phenotype closely related to CMV-specific CD8⁺ αβ T cells. In addition, human CMV-induced Vδ2⁻ γδ T cells also shared some features (highlighted in red) with CMV-induced NK cells among which the expression of CD16 and CD158.