Abstract
Invariant natural killer T (iNKT) cells are a highly conserved subset of unconventional T lymphocytes that express a canonical, semi-invariant T cell receptor and surface markers shared with the natural killer cell lineage. iNKT cells recognize exogenous and endogenous glycolipid antigens restricted by non-polymorphic CD1d molecules, and are highly responsive to the prototypical agonist, α-galactosylceramide. Upon activation, iNKT cells rapidly coordinate signaling between innate and adaptive immune cells through the secretion of proinflammatory cytokines, leading to the maturation of antigen-presenting cells, and expansion of antigen-specific CD4+ and CD8+ T cells. Because of their potent immunoregulatory properties, iNKT cells have been extensively studied and are known to play a pivotal role in mediating immune responses against microbial pathogens including viruses. Here, we review evidence that herpesviruses manipulate CD1d expression to escape iNKT cell surveillance and establish lifelong latency in humans. Collectively, published findings suggest that iNKT cells play critical roles in anti-herpesvirus immune responses and could be harnessed therapeutically to limit viral infection and viral-associated disease.
Highlights
Herpesviridae is a family of large DNA viruses that contain between 100 and 200 genes within an icosahedral capsid composed of viral proteins, mRNAs, and a lipid bilayer envelope [1]
Mounting evidence supports a significant role for Invariant natural killer T (iNKT) cells in bridging innate and adaptive immune defenses during herpesvirus infection
Given that herpesviruses interfere with CD1d–iNKT recognition empirically suggests that virus survival and persistence may benefit from the evasion of iNKT cell surveillance
Summary
Herpesviridae is a family of large DNA viruses that contain between 100 and 200 genes within an icosahedral capsid composed of viral proteins, mRNAs, and a lipid bilayer envelope [1]. Natural killer T (NKT) cells are a unique group of CD1d-restricted innate-like lymphocytes and patients deficient in NKT cells develop severe and fatal herpesvirus infections [18,19,20,21,22,23,24] These findings, in concert with observations showing that herpesviruses downregulate surface expression of CD1d [25, 26], suggest an important role for NKT cells in the immune response to herpesviruses. Herpesviruses do not express virus-specific lipids; in the absence of pathogen-derived antigens, iNKT cells likely recognize endogenous self-lipids presented by CD1d [47] Supporting this assumption are several lines of evidence showing that CD1d is required to activate iNKT cells following human herpesvirus infection [25, 48,49,50,51,52,53].
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