Going both ways: immune regulation via CD1d-dependent NKT cells

Abstract

NKT cells are a unique T lymphocyte sublineage that has been implicated in the regulation of immune responses associated with a broad range of diseases, including autoimmunity, infectious diseases, and cancer. In stark contrast to both conventional T lymphocytes and other types of Tregs, NKT cells are reactive to the nonclassical class I antigen-presenting molecule CD1d, and they recognize glycolipid antigens rather than peptides. Moreover, they can either up- or downregulate immune responses by promoting the secretion of Th1, Th2, or immune regulatory cytokines. This review will explore the diverse influences of these cells in various disease models, their ability to suppress or enhance immunity, and the potential for manipulating these cells as a novel form of immunotherapy.

Figure 1

Schematic outline as to how NKT cells influence the immune response in either a Th1 or Th2 direction. (A) Environmental model. The green side shows factors supporting the Th1 responsiveness by NKT cells, while the red side shows factors supporting Th2 responsiveness by these cells. The environment in which NKT cells are found, including the type of cytokines and APCs and the strength of antigen-mediated TCR stimulation they receive, determines the cytokine output. Upregulation of cell-surface CD40L by NKT cells stimulates IL-12 release by DCs, which work together with NKT cell–derived IFN-γ to stimulate Th1 responses. IL-7 has been reported to enhance Th2 cytokine production by NKT cells, while cell-surface molecules that mediate immune suppression or Th2 deviation by these cells have not been identified. Time after stimulation may also be an important factor, as NKT cells also tend to produce Th1- and Th2-like cytokines in the short term (1–3 hours) following stimulation but may then switch to a Th1 output, which can last for several days. (B) Subset model. Preexisting subsets of NKT cells are programmed to produce different ratios of Th1/Th2 cytokines, as reported for CD4^– and CD4⁺ human NKT cells. In this case, the influence of NKT cells on the immune response would depend on the prevalence and/or relative involvement of these 2 subsets. The 2 models are not necessarily mutually exclusive.