Cytomegalovirus immune evasion sets the functional avidity threshold for protection by CD8 T cells

Abstract

Conflicting hallmarks are attributed to cytomegalovirus (CMV) infections. CMVs are viewed as being master tacticians in “immune evasion” by subverting essentially all pathways of innate and adaptive immunity. On the other hand, CMV disease is undeniably restricted to the immunologically immature or immunocompromised host, whereas an intact immune system prevents virus spread, cytopathogenic tissue infection, and thus pathological organ manifestations. Therefore, the popular term “immune evasion” is apparently incongruous with the control of CMV infections in the immunocompetent human host as well as in experimental non-human primate and rodent models. Here, we review recent work from the mouse model that resolves this obvious discrepancy for the example of the virus-specific CD8 T-cell response. Immune evasion proteins encoded by murine CMV (mCMV) interfere with the cell surface trafficking of antigenic peptide-loaded MHC class-I (pMHC-I) complexes and thereby reduce their numbers available for interaction with T-cell receptors of CD8 T cells; but this inhibition is incomplete. As a consequence, while CD8 T cells with low interaction avidity fail to receive sufficient signaling for triggering their antiviral effector function in the presence of immune evasion proteins in infected cells, a few pMHC-I complexes that escape to the cell surface are sufficient for sensitizing high-avidity CD8 T cells. It is thus proposed that the function of immune evasion proteins is to raise the avidity threshold for activation, so that in the net result, only high-avidity cells can protect. An example showing that immune evasion proteins can make the difference between life and death is the lacking control of infection in a mouse model of MHC-I histoincompatible hematopoietic cell transplantation (allogeneic-HCT). In this model, only low-avidity CD8 T cells become reconstituted by HCT and almost all infected HCT recipients die of multiple-organ CMV disease when immune evasion proteins are expressed. In contrast, lowering the avidity threshold for antigen recognition by deletion of immune evasion proteins allowed control of infection and rescued from death.

T‐cell heterogeneity, progenitor–progeny relationships, and function during latent and chronic viral infections

“…CMVs express a number of immune evasion genes, some of which specifically target the MHC class I presentation pathway (reviewed in Ref. 204 ), posing a challenge for the priming of CMV-specific CD8 T cells by directly infected antigen-presenting cells (APCs). Thus, crosspresentation of CMV antigens by hematopoietic cells, specifically CD8 + and/or CD103 + DCs, was shown to be indispensable for the efficient priming of CD8 T cells in MCMV infection.…”

“…CMVs express a number of immune evasion genes, some of which specifically target the MHC class I presentation pathway (reviewed in Ref 204 …”

Chimeric antigen receptor engineered cells and their clinical application in infectious disease

“…It plays a significant role in postoperative recovery and graft survival 180 . CMVs are considered to have evolved effective mechanisms to down‐regulate MHC and prevent peptide presentation, therefore being a master in ‘immune evasion’ 181 …”

“…180 CMVs are considered to have evolved effective mechanisms to down-regulate MHC and prevent peptide presentation, therefore being a master in 'immune evasion'. 181…”

Editorial on special issue on “Immunobiology of Viral Infections”

“…Cytomegaloviruses (CMV) are masters of controlling both the innate and the adaptive immune responses. As reviewed by Hamdan et al, cytomegaloviruses are controlled by the immune system, but are still able to establish latency [ 4 ]. Reactivation of the virus poses a problem, especially in immunocompromised hosts.…”