UC San Diego
The Signals that Regulate Cytokine Production by Natural Killer T Cells
- Author(s): Nagarajan, Niranjana Aditi
- et al.
Natural Killer T (NKT) cells influence many immune processes through the production of cytokines, and the research described in this dissertation is directed towards elucidating the signals that regulate cytokine production by these cells. Antigen presentation is a known regulator of T cell responses and the requirements for CD1d-mediated antigen presentation were investigated. These studies demonstrate that CD1d requires lysosomal trafficking in order to present glycosphingolipid (GSL) antigens to NKT cells, and that this trafficking is mediated by the interaction of the cytoplasmic tail of CD1d with the adaptor protein complex AP-3. The nature of the GSL antigen used is also known to affect NKT cell cytokine production, and structurally modified altered glycolipid ligands were used to characterize effect of altering antigen avidity and affinity on cytokine production. The model antigen used to stimulate NKT cells, [alpha]galactosylceramide ([alpha]GalCer), induces an unbiased TH0 response, with equivalent production of interferon-γ (IFN[gamma]) and interleukin (IL)-4 by these cells. OCH, a variant of [alpha]GalCer that induces a TH2-biased systemic response, activates NKT cells to a similar degree as [alpha]GalCer. The mechanism of this altered activation is unclear, as OCH induces a similar degree of early signaling as [alpha]GalCer although it associates with the TCR with lesser avidity, suggesting that while OCH may not alter NKT cell activation, it affects the downstream activation of other cells. C-glycoside, a variant of [alpha]GalCer that induces a TH1-biased response, is a poor early activator of NKT cells, inducing low early signaling and binding the TCR with low affinity and avidity, probably inducing low, sustained signaling that results in a systemic TH1 response. These studies also demonstrate that NKT cells respond to bacterial lipopolysaccharide (LPS), and that their response to LPS is polarized, with exclusively IFN[gamma] and no IL-4 being produced. NKT cells do not express toll-like receptor-4 and respond indirectly, to IL -12 and IL-18 produced in response to LPS. NKT cells are also critical for the systemic response to LPS, and mice that are genetically deficient for NKT cells exhibit severely impaired production of pro-inflammatory cytokines