CD1d Expression and Invariant NKT Cell Responses in Herpesvirus Infections

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.

Editorial: CD1- and MR1-Restricted T Cells in Antimicrobial Immunity

“…Viruses do not possess lipid ligands for i NKT cell TCRs. However, infection with some viruses (e.g., dengue virus) leads to upregulated CD1d expression consistent with i NKT cell activation while certain others (e.g., herpesviruses and HIV) downregulate CD1d to plausibly evade detection by i NKT cells ( 30 , 31 ). Viral infection may also induce a shift in host cell lipid profiles, thus yielding more “antigenic” CD1d ligands ( 32 ).…”

CD1-Restricted T Cells During Persistent Virus Infections: “Sympathy for the Devil”

“…It has been shown that iNKT cells contribute to antiviral responses although the relevant lipid antigens have not yet been defined [recently reviewed in Ref. ( 33 – 37 )].…”

“…During the evolutionary arms race with the host immune system persisting viruses have developed multilayered defense strategies to interfere with antiviral CD1-restricted T cells ( 17 , 33 , 35 , 36 , 227 ). They target the CD1 antigen presentation machinery either on the transcriptional, posttranscriptional, or posttranslational level.…”

CD1d highly expressed on DCs reduces lung tumor burden by enhancing antitumor immunity

“…CD1d has been declared as a regulator in immune disorders such as infection, autoimmune and inflammatory diseases. By targeting NKT cells, CD1d has been revealed to function as a suppressor in tumors (11–15). Although CD1d can be expressed by cells of both myeloid (monocytes and macrophages) and lymphoid lineages (16,17), as well as non-hematopoietic cells (e.g., epithelial and vascular smooth muscle cells), it is still unclear which cells are the major source of CD1d in tumors.…”