Natural killer T-cell autoreactivity leads to a specialized activation state

Abstract

Natural killer T (NKT) cells are innate-likeT cells that recognize specific microbial antigens and also display autoreactivity to self-antigens. The nature of NKT-cell autoreactive activation remains poorly understood. We show here that the mitogenactivated protein kinase (MAPK) pathway is operative during human NKT-cell autoreactive activation, but calcium signaling is severely impaired. This results in a response that is biased toward granulocyte macrophage colony-stimulating factor (GM-CSF) secretion because this cytokine requires extracellular signalregulated kinase (ERK) signaling but is not highly calcium dependent, whereas interferon-␥ (IFN-␥), interleukin (IL)-4, and IL-2 production are minimal. Autoreactive activation was associated with reduced migration velocity but did not induce arrest; thus, NKT cells retained the ability to survey antigen presenting cells (APCs). IL-12 and IL-18 stimulated autoreactively activated NKT cells to secrete IFN-␥, and this was mediated by Janus kinase-signal transducers and activators of transcription (JAK-STAT)-dependent signaling without induction of calcium flux. This pathway did not require concurrent contact with CD1d ؉ APCs but was strictly dependent on preceding autoreactive stimulation that induced ERK activation. In contrast, NKT-cell responses to the glycolipid antigen ␣-galactosyl ceramide (␣-GalCer) were dampened by prior autoreactive activation. These results show that NKT-cell autoreactivity induces restricted cytokine secretion and leads to altered basal activation that potentiates innate responsiveness to costimulatory cytokines while modulating sensitivity to foreign antigens. (Blood. 2008;112: 4128-4138) IntroductionNatural killer T (NKT) cells are a subset of regulatory T cells that recognizes lipid antigens presented by CD1d molecules. 1,2 Like innate lymphocytes, NKT cells are among the first responders during microbial infections, and their responses are not necessarily dependent on recognition of foreign antigens. 3 NKT cells have attracted attention because they secrete large amounts of both Th1 and Th2 cytokines rapidly on stimulation and demonstrate a potent ability to modulate immune function. 1,2,4 Remarkably, in some disease models, NKT cells promote proinflammatory immune responses, whereas in others they have a tolerogenic effect. 5 It is not clear what confers the innate-like features of NKT cells or how they mediate contrasting immunologic outcomes in different contexts.Most NKT cells can be activated to secrete cytokines by exposure to CD1d ϩ antigen-presenting cells (APCs) in the absence of microbial antigens, and this appears to depend on presentation of cellular antigens by CD1d. 6-9 NKT cells from germ-free mice and from human cord blood display a phenotype indicating prior activation, [10][11][12] suggesting that NKT cells are autoreactive to self-antigens in vivo. NKT cells have been shown to recognize certain mammalian lipids as antigens presented by CD1d 9,13 ; however, the specific self-antigens responsible for NKT cell autorea...

Human NKT cells promote monocyte differentiation into suppressive myeloid antigen-presenting cells

“…The lower-well cells were then harvested for use in the analyses described below. Because we have found that human NKT cells that are activated by recognition of auto-antigens mainly secrete GM-CSF and IL-13, whereas those that are stimulated by ␣-GalCer also secrete other cytokines (such as IFN-␥ and IL-4) that may influence monocyte differentiation [49], we compared NKT-instructed APCs in which the NKT cells were stimulated by untreated monocytes (i.e., presenting auto-antigen), with those that differentiated in response to NKT cells that were stimulated by ␣-GalCer pulsed monocytes.…”

“…We have previously found that NKT cells that are activated by recognition of auto-antigens secrete little or no IFN␥ or IL-4, whereas those that are activated by the potent agonist ␣-GalCer robustly produce these cytokines [43,49]. Since exposure to IFN-␥ has been associated with enhancing IL-12p70 production by myeloid DCs, we investigated whether the route of NKT cell activation influences the pattern of cytokine production by the resulting APCs.…”

Fine tuning by human CD1e of lipid-specific immune responses

“…These effects were observed with two different types of transfectants (THP-1 and C1R), excluding unique behavior associated with the nature of APCs. The differential influence on the type of released cytokines probably reflects the reported different signal strength required for secretion of GM-CSF versus IL-4 and IFN-γ (12). The presence of CD1e might influence the number and nature of CD1-antigen complexes, leading to a reduced TCR signal strength that might affect IFN-γ production more readily than that of GM-CSF.…”

“…CD1e might directly influence the number of CD1d-antigen complexes available over time, which has been shown to affect the type of cytokines released (12)(13)(14). To test this possibility, antigen-pulse experiments were performed to compare the time required for the generation of CD1d-antigen stimulatory complexes.…”

Nonclassical T Cells and Their Antigens in Tuberculosis

“…iNKT cells contain preformed IFN-g mRNA in their cytoplasm, which promotes immediate secretion of this cytokine on TCR stimulation at levels 200 times higher than conventional MHC-restricted CD4 þ T cells (Stetson et al 2003). This secretion of cytokines is controlled by the strength of TCR signal received during antigen recognition (Wang et al 2008), which depends on the number of CD1 complexes as well as their persistence on the surface of APCs. In addition, human NKT cells express granulysin (Gansert et al 2003) that participates in killing intracellular bacteria resident within target cells.…”