Microbes and Infection 12 (2010) 1125e1133www.elsevier.com/locate/micinf

Review

Natural killer T cells: innate lymphocytes positioned as a bridge betweenacute and chronic inflammation?

Lisa Fox, Subramanya Hegde, Jenny E. Gumperz*

Department of Medical Microbiology and Immunology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

Received 10 August 2010; accepted 27 August 2010

Available online 17 September 2010

Abstract

Natural killer T cells are an innate population of T lymphocytes that recognize antigens derived from host lipids and glycolipids. In thisreview, we focus on how these unique T cells are positioned to influence both acute and chronic inflammatory processes through their earlyrecruitment to sites of inflammation, interactions with myeloid antigen presenting cells, and recognition of lipids associated with inflammation.� 2010 Institut Pasteur. Published by Elsevier Masson SAS. All rights reserved.

Keywords: NKT cells; CD1d; Inflammation; Lipid mediators

1. Introduction

While inflammation has long been recognized as a funda-mental set of host responses that are involved in most types ofmicrobial infection, the pathways linking inflammation andantigen-specific immune functions remain poorly understood.Persistent inflammation, a source of much disease pathology, isoften associated with the disregulated activation of antigen-specific lymphocytes, and therefore understanding the processesthat link adaptive immunity to inflammatory responses isa question of great importance. In this review, we bring togethera series of findings suggesting that a population of innatelymphocytes called Natural Killer T (NKT) cells is uniquelypositioned to regulate both the early innate processes ofinflammation and the induction of later adaptive responses.

2. A brief overview of inflammation

Inflammation involves a coordinated series of events that canbe divided into two parts, called the “acute” and “chronic”phases (see Fig. 1). The acute phase of an inflammatoryresponse is generally initiated by the activation of tissue-

* Corresponding author. Tel.: þ1 608 263 6902; fax: þ1 608 262 8418.

E-mail address: jegumperz@wisc.edu (J.E. Gumperz).

1286-4579/$ - see front matter � 2010 Institut Pasteur. Published by Elsevier Ma

doi:10.1016/j.micinf.2010.08.011

resident sentinel cells, such as macrophages, dendritic cells(DCs), and mast cells, as a result of their recognition of danger-associated molecules (e.g. microbial compounds). These cellsrapidly release soluble effector molecules, including lipidmediators, vaso-active peptides, cytokines, and chemokines.These soluble factors work together to increase vasodilationand vascular permeability, and to recruit neutrophils andplatelets to the site of inflammation. Once in the tissues,neutrophils assist in clearing the source of the inflammationthrough phagocytosis of bacteria and dead host cells andthrough the release of bactericidal agents, while platelets caninitiate wound healing.

The chronic phase involves inflammatory processes that arecoordinated by T lymphocytes. This phase starts with the traf-ficking of antigen presenting cells (APCs) to lymphoid tissues,carrying antigens from the site of inflammation (Fig. 1). Withinlymphoid tissues, the APCs (i.e. dendritic cells or macro-phages) present the inflammation-associated antigens to T cellsand provide critical additional stimuli such as co-stimulatoryligands and cytokines. This results in the differentiation andproliferation of antigen-specific effector T cells that leave thelymphoid tissue and infiltrate the site of inflammation. There,they produce effector cytokines such as IFN-g or IL-17 thatboth enhance the activation and bactericidal effects of phago-cytic cells and prolong their inflammatory functions [1].

sson SAS. All rights reserved.

Fig. 1. Overview of inflammation. Upon wounding or a bacterial infection, tissue-resident myeloid cells (macrophages and DCs) and mast cells become activated

and produce a variety of cytokines, chemokines, vasoactive peptides, and lipid mediators. This results in vasodilation, enhanced vascular permeability, and the

activation of platelets. These molecules also recruit neutrophils into the tissues, where they become activated. This constitutes the acute phase of inflammation. The

initiation of the chronic phase of inflammation begins when myeloid APCs migrate to secondary lymphoid tissues, where they present antigens to T lymphocytes

and provide critical additional signals (e.g. expression of co-stimulatory molecules and production of cytokines). Antigen-specific T lymphocytes become activated

and migrate to the source of inflammation, where they secrete cytokines that enhance to phagocytic and bacteriocidal properties of macrophages, neutrophils, and

other cells. The continuous activation of neutrophils prevents them from undergoing apoptosis, and can lead to a persistent inflammatory state.

1126 L. Fox et al. / Microbes and Infection 12 (2010) 1125e1133

Acute inflammatory processes are generally self-resolving,in part because this response is mediated by compounds suchas bioactive lipids that have short half-lives and are quicklydegraded [2], and in part because many of the lipid mediatorpathways include compounds that actively inhibit the laterstages of inflammation [3]. In contrast, while the chronic phaseof inflammatory responses can provide a powerful boost thathelps to rapidly clear the infection and resolve the inflam-mation, if it is not properly controlled this phase can lead toa persistent inflammatory state, characterized by tissuedamage mediated by leukocytes and lymphocytes [4].

Perhaps the best examples of persistent inflammatory statesthat involve antigen-specific chronic inflammation are auto-immune diseases such as type I diabetes and multiple scle-rosis. While the role of microbial infection and acuteinflammation in the etiology of these diseases remains poorly

understood, it is clear that the persistent activation of antigen-specific autopathogenic T cells is central to their diseasepathologies. What is also clear is that the chronic inflamma-tory states that develop in these autoimmune diseases can becounterbalanced by the actions of regulatory T cells thatinhibit the effects of autopathogenic T cells. One population ofT cells that has been shown to be able to regulate the auto-immune pathology of type I diabetes and multiple sclerosis isthe Natural Killer T (NKT) subset (reviewed in Refs. [5,6]).

3. NKT cells regulate inflammatory responses

NKT cells are an innate T lymphocyte population thatrecognizes lipid antigens presented by the non-classicalantigen-presenting molecule CD1d, which is expressed onmyeloid cell types including monocytes, macrophages, and

1127L. Fox et al. / Microbes and Infection 12 (2010) 1125e1133

DCs [7,8]. What is remarkable about NKT cells is that theynot only can inhibit autoimmune disease by autopathogenic Tcells, but they can also promote pro-inflammatory antigen-specific T cell responses, as evidenced by their ability toenhance the reactions of MHC-restricted T cells to proteinantigens that were delivered as vaccines [9]. Moreover, NKTcells can enhance the pro-inflammatory functions of otherinnate lymphocyte subsets such as natural killer (NK) cells[10e12], and they contribute to the clearance of a variety ofmicrobial infections (reviewed in Refs. [13e15]). The con-trasting immunological effects of NKT cells have been relatedto their secretion of both Th1 and Th2 cytokines, and, perhapsmore importantly, to their ability to interact in varied wayswith key APCs (reviewed in Ref. [16]). However, what theirdisparate effects in different immunological contexts alsoclearly suggest is that NKT cells are best characterized asregulatory cells that contribute to multiple aspects of inflam-matory responses.

A number of observations suggest that the role of NKTcells may start during the acute phase of inflammation. Theseinclude the finding that most circulating human NKT cellsexpress a pattern of chemokine receptors that is characteristicof T cells that home to sites of inflammation [17e19].Moreover, both NKT cells and CD1dþ APCs have been foundto be enriched at sites of peripheral inflammation, such asperiodontal lesions [20,21]. Additionally, we have recentlyshown that a significant fraction of human NKT cells recog-nize the presentation by CD1d molecules of a lipid calledlyso-phosphatidylcholine (LPC), which is produced by phos-pholipase A2 (PLA2) enzymes during the initiation ofinflammatory lipid mediator cascades [22]. Together, theseobservations suggest that circulating NKT cells may be rapidlyrecruited to sites of inflammation, and may become specifi-cally activated by CD1d-mediated presentation of lipid anti-gens that are produced there.

Consistent with this picture, a recent report demonstratesthat NKT cells are constituents of the early inflammatoryinfiltrate in a murine excisional wounding model [23]. TheNKT cells were present as early as 12 h post-wounding,coinciding with the infiltration of neutrophils. Several studies

Fig. 2. Determinants of cytokine output. Although NKT cells are capable of produ

given situation depend on a number of different variables. These include: the lev

presented (2). These factors determine the strength of the signal received through t

less TCR stimulation, with IL-4, IFNg, and IL-2 production requiring a stronger sti

(4) can amplify NKT cell responses to weak or rare antigens, and stimulate the pr

have also indicated that NKT cells may have an impact onneutrophil recruitment or activation during the early stages ofbacterial infections. In a murine model of acute pneumonia,CD1d�/� mice, which lack NKT cells, showed poor clearanceof Pseudomonas aeruginosa [24]. This appeared to be asso-ciated with markedly reduced influx of neutrophils into thelungs during the early stages of infection [24], althougha different analysis of P. aeruginosa infection failed to confirmthis neutrophil recruitment defect [25]. However, mice that arespecifically deficient in the NKT cell subset did show a defectin neutrophil recruitment into the lungs within the first 12 hafter infection with Streptococcus pneumoniae [26], and theneutrophil recruitment defect in this S. pneumoniae modelcould be corrected by adoptive transfer of liver mononuclearcells containing NKT cells but not by transfer of cells fromNKT-deficient mice [27]. Moreover, data from this modelsuggest that production of IFN-g by NKT cells early in thecourse of the infection may have a critical role in activatingthe neutrophil-mediated host defense [27].

Thus, it seems likely that the functions of NKT cells mayfirst come into play during the acute phase and span thetransition to chronic inflammatory responses. In the followingsections we will first discuss what is known about how NKTcells become activated and interact with myeloid APCs, andwill then go on to consider how they may contribute to cellularevents at the site of inflammation.

4. NKT cell activation

Although NKT cells are known for their ability to producea wide variety of cytokines, they do not necessarily do this inevery activation scenario. The specific cytokines produced byNKT cells in any given situation are dependent on a number offactors. A critical component is the level of CD1d expressed bythe APC, along with the identity and abundance of the antigenspresented. These variables all come together to determine thestrength of the T cell receptor (TCR) stimulation experiencedby the NKT cell (Fig. 2). We have found that whereas humanNKT cells produce a range of cytokines (e.g. GM-CSF, IL-13,IFN-g, IL-4, IL-2) in response to strong TCR stimulation

cing a wide variety of cytokines [17], the specific cytokines produced in any

el of CD1d expressed by the APC (1) and the type and quantity of antigen

he TCR (3), which in turn directs cytokine output: GM-CSF and IL-13 require

mulus [28]. The presence of co-stimulating cytokines such as IL-12 and IL-18

oduction of IFNg [28].

1128 L. Fox et al. / Microbes and Infection 12 (2010) 1125e1133

resulting from exposure to high doses of a high affinity antigen,they produce a more limited set (mainly GM-CSF and IL-13) inresponse to low levels of TCR stimulation [28]. Additionally,the responses of NKT cells are influenced by cytokines presentin the environment (Fig. 2). For example, the presence of IL-12p70 and IL-18 (cytokines that are made by activated myeloidAPCs) can compensate for the lack of a strong TCR agonist anddrive NKT cells to secrete IFN-g [28].

Another complexity is the source of antigens that physio-logically activate NKT cells. Whereas most peripheral T cellshave been subjected to thymic selection ensuring that theyhave little ability to specifically recognize self antigens, itseems that it is a normal part of the biology of peripheral NKTcells that they are able to specifically recognize certain selfmolecules as antigens, as well as recognizing specific micro-bial lipids (reviewed in Refs. [7,14,29]). As a result, NKT cellscan be activated by at least two different pathways duringinfections (Fig. 3). In one route, called the “direct” pathway, itis the recognition of specific microbial lipids that have beeningested and loaded onto CD1d molecules that is thought tostimulate the NKT cell [30e32]. Alternatively, in the “indi-rect” pathway of NKT cell activation, a foreign lipid need notbe present if sufficient pro-inflammatory cytokines areproduced by APCs [33e35]. Thus, the direct pathway of NKTcell activation could represent a case in which a strong TCRagonist is present, while the indirect pathway may representa situation in which TCR stimulation is weak but iscompensated by the presence of co-stimulatory cytokines.

The prototypical NKT cell “foreign” antigen is a glyco-sphingolipid called a-galactosylceramide (a-GalCer). Thislipid was originally isolated from non-sterile samples ofa marine sponge [36] (thus, it is not clear whether a-GalCeractually derives from the sponge or from bacteria that hadcolonized it), and has been shown to act as a strong agonist for

Fig. 3. Activation by lipid antigens. NKT cells can be activated to produce IFN-g

recognition of self lipids that are presented along with co-stimulating cytokines

recognition receptor (PRR), such as one of the toll-like receptors (TLR). Notably, th

APCs resulting in presentation by the direct pathway may involve TLR-stimulation,

not displace all of the self-antigens presented by the CD1d molecules on an APC, an

despite the presence of foreign microbial compounds.

NKT cells [37]. Mammalian cells do not appear to produceglycosphingolipids of this type in which the sugar is linked inan a-conformation to the lipid, and so a-GalCer is not thoughtto represent an analogue of self antigens recognized by NKTcells. However, structurally similar glycosphingolipids that areantigenic for NKT cells have been isolated from the cell wallsof several Sphingomonas bacterial species [30,32,34]. Addi-tionally, diacylglycerol lipids containing an a-linked galactosehave been isolated from the spirochete Borrelia burgdorferiand been shown to be recognized by NKT cells in a CD1d-dependent manner [31]. Other microbial lipids that may beantigenic for NKT cells include mycobacterial phosphatidy-linositol mannosides, lipophosphoglycan from Leishmaniadonovani, and lipopeptidophosphoglycan from Entamoebahistolytica [38e40].

What is striking about all of the microbial lipid antigensthat have been identified thus far, however, is that none ofthem seem to be particularly strong TCR agonists for NKTcells (certainly none are as potent as a-GalCer). Thus, it is notclear that foreign lipids generally do stimulate NKT cellsmainly through the direct pathway. Instead, it seems likely thatin many cases CD1d-mediated presentation of foreign micro-bial lipids takes place concurrently with presentation of selflipids that may also be antigenic, and is carried out by APCsthat are producing co-stimulatory cytokines, such as IL-12 andIL-18, as a result of pattern recognition receptor-inducedactivation by the microbial compounds that they have ingested(Fig. 3). This scenario is illustrated by a recent analysis ofNKT cell activation by lipopeptidophosphoglycan fromE. histolytica, which found that NKT cell IFN-g productionwas dependent both on access to CD1d and on toll-likereceptor (TLR) stimulated production of IL-12 by the APCs[40]. Thus, since many microbial lipids may constitute onlyrelatively weak TCR agonists for NKT cells, an inflammatory

either by “direct” recognition of foreign microbial antigens, or “indirectly” by

produced by myeloid APCs that have received stimulation through a pattern

ese pathways are not mutually exclusive. In many cases, lipid antigen uptake by

and cytokine production by the APCs. Moreover, foreign antigens probably do

d thus NKT cells may continue to be stimulated by recognition of self-antigens

1129L. Fox et al. / Microbes and Infection 12 (2010) 1125e1133

milieu may be required for NKT cell activation by manyforeign antigens.

To add another twist to the plot, however, several studieshave now come out that point to pathways by which NKT cellsmay become specifically activated by self-antigens that are up-regulated during inflammatory responses. We recently repor-ted that human NKT cells are capable of responding to LPC asan antigen presented by CD1d molecules [22]. LPC isgenerated by PLA2-mediated cleavage of membrane phos-phatidylcholine (PC) molecules, which is a critical initiatingevent in the biosynthesis of eicosanoid lipid mediators. Uponexposure of myeloid APCs to inflammatory stimuli, one of theearliest cellular responses is the activation of PLA2 enzymes[41,42]. The resulting release of arachidonic acid serves asa substrate for the biosynthesis of eicosanoids by two familiesof enzymes, cycloxygenases and lipoxygenases, whichgenerate prostanoids and leukotrienes, respectively [2,43].Eicosanoid lipid mediators such as these are released in largequantities during inflammatory responses and perform criticalfunctions at sites of inflammation, such as influencing localblood flow and vascular permeability and serving as chemo-attractants for neutrophils and monocytes. Interestingly, wefound that human peripheral blood monocytes that were pre-treated with an antibody against secreted PLA2 had unalteredlevels of cell surface CD1d, yet were unable to stimulate LPC-

Fig. 4. Effects of inflammatory lipids. A) NKT cells recognize specific lipids that

Microbial stimulation of myeloid antigen presenting cells results in the activation of

membranes, releasing lyso-phosphatidylcholine (LPC). LPC can bind to CD1d mole

microbial stimulation of myeloid APCs alters the types of glycosphingolipids prese

NKT cells [44e46]. B) Because of their early recruitment to sites of inflammation

have been shown to express the PGD2 receptors DP1 and DP2, and to respond to

reducing secretion of IFN-g but not IL-4 [47].

reactive NKT cells, suggesting that the antibody treatmentblocked their ability to present this self antigen [22]. Thus,based on our data, it is reasonable to speculate that theenzymatic activity of PLA2 molecules secreted by myeloidAPCs at sites of inflammation may lead to increased presen-tation of LPC by their cell surface CD1d molecules, and thatthis might enhance the activation of NKT cells, perhaps to thepoint of inducing cytokines such as IFN-g and IL-2 that areproduced upon exposure to strong TCR signaling (Fig. 4A).

An alternative process by which NKT cell activation may beenhanced during inflammation is suggested by recent findingsshowing that exposure of myeloid antigen presenting cells toTLR ligands results in changes to cellular glycosphingolipidspresented by CD1d molecules and these altered self lipids mayprovide enhanced stimulation to NKT cells (Fig. 4A). Onestudy found that under physiological conditions, the ganglio-sides (a type of mammalian glycosphingolipid) bound tomurine CD1d molecules were predominantly composed of thespecies GM1a, GD1a, and GM2. However, upon stimulationwith LPS the composition of the lipids bound to CD1dchanged, such that GM3 and GD1a were the main species [44].In another analysis, several of the enzymes involved in thesynthesis of cellular glycosphingolipids were up-regulatedupon CpG stimulation of APCs, and charged lipids isolatedfrom these APCs appeared to be antigenic for NKT cells [45].

are produced during inflammation as antigens presented by CD1d molecules.

secreted PLA2 enzymes. These cleave phosphatidylcholine molecules in lipid

cules, and is recognized as an antigen by human NKT cells [22]. Additionally,

nted by CD1d molecules, and this may result in increased TCR stimulation of

, NKT cells may be targets for lipid mediators produced by APCs. NKT cells

stimulation through these receptors by altering their migration and selectively

1130 L. Fox et al. / Microbes and Infection 12 (2010) 1125e1133

Finally, Salio and colleagues demonstrated that treatment ofDCs with a variety of TLR agonists led to increased NKT cellresponses that were correlated with increased expression ofseveral enzymes involved in the biosynthesis of glyco-sphingolipids of the ganglio and globo series [46]. Moreover,fluorescent tetramers made from an NKT cell TCR showedincreased binding to TLR-stimulated APCs even though thecell surface CD1d levels were not increased, providing directevidence to support the hypothesis that a change had takenplace that increased the TCR agonism provided by the selflipids bound to the cell surface CD1d molecules. Thus,together these studies suggest that inflammatory processes mayincrease the abundance or affinity of self-antigens presented byCD1d.

Given that NKT cells may be present from quite early on atsites of inflammation, and may be interacting with CD1dþ

APCs in this context, it seems reasonable to suppose that NKTcells themselves may be targets of lipid mediators (Fig. 4B).This question has only recently started to be explored,however, a recent analysis showed that murine NKT cellsexpress mRNA for two membrane receptors for prostaglandinD2 (PGD2), termed D prostanoid receptor 1 (DP1) and DP2

Fig. 5. Modulation of myeloid APCs. A) Upon recognition of antigen presented b

produce cytokines such as IFN-g and TNF-a. Stimulation of myeloid APCs thro

expression of co-stimulatory molecules (e.g. CD80 and CD86) and altered prod

a profound effect on their ability to subsequently stimulate antigen-specific MHC-

stimulation may influence the types of lipid mediators produced by myeloid APC

recognition of antigens presented by CD1d, have been reported to impact expressi

55]. Additionally, stimulation of myeloid APCs through CD40 induces activatio

cyclooxygenase-2 enzymes resulting in altered prostaglandin production [58].

[47]. Using specific agonists for these receptors, the authorsshowed that they influence the chemotactic migration of NKTcells, and also demonstrated that exposure to PGD2 resulted ina selective reduction of NKT cell IFN-g production while IL-4secretion was not affected [47]. Whether NKT cell responsesare also affected by other lipid mediators that may beproduced at sites of acute inflammation is a question thatremains to be determined.

5. Modulation of myeloid APC functions

It is now well established that NKT cells are able tointeract with a variety of types of myeloid APCs, and canmarkedly modulate their functional characteristics (recentlyreviewed in Ref. [16]). The major pathways by which NKTcells enhance the pro-inflammatory functions of myeloidAPCs include co-stimulation by CD40L, and production ofcytokines such as IFN-g and TNF-a (Fig. 5A). In turn, thesestimuli cause DCs to mature, up-regulate their own co-stimulatory ligands (e.g. CD80 and CD86), and to maintainlong-lasting production of the pro-inflammatory cytokine IL-12p70 [48,49]. It has been clear for some time that induction

y CD1d, NKT cells up-regulate their cell surface expression of CD40L, and

ugh ligation of CD40 and recognition of these cytokines results in increased

uction of cytokines such as IL-10 and IL-12. These APC changes can have

restricted T cells [48, 50, 51]. B) Similar pathways of NKT cell-mediated co-

s. The cytokines IL-4 and IL-13, which can be produced by NKT cells upon

on of lipoxygenase enzymes involved in the generation of lipid mediators [54,

n of NFkB and MAPK signaling processes that can influence expression of

1131L. Fox et al. / Microbes and Infection 12 (2010) 1125e1133

of NKT-mediated pathways of DC stimulation by adminis-tration of the synthetic glycolipid a-GalCer can haveprofound effects on adaptive T cell responses to proteinantigens [50,51], and more recent studies now suggest thatphysiologically activated NKT cells may mediate similareffects during microbial infections. For example, it wasrecently demonstrated in a model of Chlamydia pneumoniaeinfection that the myeloid DCs from mice specifically lack-ing in NKT cells showed lower expression levels of thematuration markers CD40, CD80, and MHC class II, and alsosecreted less IL-12 than DCs from NKT cell sufficient mice[52]. Moreover, in a murine model of influenza A infection,NKT cells appeared to relieve the tolerogenic effects ofmyeloid derived suppressor cells via CD40L co-stimulation,ultimately resulting in enhanced anti-viral immune responses[53]. Thus, NKT cells that interact with myeloid APCs atsites of inflammation may enhance their ability to stimulateadaptive T cell responses after trafficking to secondarylymphoid tissues (see Figs. 1 and 6).

An intriguing question that remains unresolved, however, iswhether NKT cells might also influence the acute phase ofinflammatory responses via similar pathways (Fig. 5B). Forexample, several of the cytokines that NKT cells can produceare known to impact lipid mediator production by myeloidAPCs. Exposure of monocytes and DCs to IL-4 is reported to

Fig. 6. NKT cells influence both the acute and chronic branches of inflammation. B

particularly well positioned to influence both the acute and chronic phases of infla

support this model, as they have been shown to impact the recruitment and/or activa

during microbial infections.

increase the expression of the enzyme 15-lipoxygenase and,conversely, to have an inhibitory effect on expression of theenzyme 5-lipoxygenase [54,55]. Both lipoxygenase enzymesmetabolize arachidonic acid, but the outcome is different:5-lipoxygenase activity leads to the biosynthesis of leukotrieneB4, a chemoattractant for neutrophils, whereas 15-lip-oxygenase activity leads to the generation of lipoxins, whichhelp mediate the resolution of inflammation. Interestingly,exposure to IL-13 might enhance the effects of IL-4, since thiscytokine has been shown to increase the expression of cyto-plasmic forms of PLA2, possibly leading to the generation ofmore arachidonic acid substrate for eicosanoid biosynthesis[56]. Additionally, IL-13 treatment has been shown to inhibitthe induction of cyclooxygenase-2 enzymes, thus limitingprostaglandin production, which could have the effect ofenhancing the biosynthesis of leukotrienes by lipoxygenases[57]. Ligation of CD40 on human monocytes has been foundto result in ERK and p38 MAPK signaling as well as inactivation of the transcription factor NFkB, and to result inincreased synthesis of PGE2 by cyclooxygenase-2 enzymes,although this effect was modulated by exposure to IL-4 [58].Thus, it may be quite reasonable to suppose that NKT cellsdirectly regulate acute inflammatory responses by exertingeffects on the lipid mediator production of myeloid APCs atsites of inflammation.

y interacting with myeloid APCs at sites of inflammation, NKT cells may be

mmatory responses. Current data on the immunological effects of NKT cells

tion of neutrophils as well as the induction of antigen-specific T cell responses

1132 L. Fox et al. / Microbes and Infection 12 (2010) 1125e1133

6. Concluding remarks

Although NKT cells comprise a comparatively small frac-tion of the total T lymphocyte population, they are now clearlyrecognized as a potent immunoregulatory population. Theiroutsized ability to influence immunological outcomes has beenattributed to their rapid cytokine production and to their abilityto modulate the functions of critical APCs. In this review, webring together results that suggest an additional reason for thefar-reaching effects of NKT cells: as a result of their earlyrecruitment to sites of inflammation and recognition of lipidantigens produced during inflammation, they may be uniquelypositioned to interact with key APCs in a way that spans theacute and chronic phases of inflammation (Fig. 6). This pictureof NKT cells raises a number of interesting questions for futureresearch, including understanding their influence on lipidmediator production by myeloid APCs and, conversely, deter-mining how the functions of NKT cells are influenced by lipidmediators produced at sites of inflammation. Also of interest,do NKT cells interact directly with other key cell types found atsites of inflammations, such as mast cells, neutrophils, plate-lets? Finally, a full understanding of the role of NKT cells ininflammatory contexts will involve assessing the significance ofother, related T cell populations that may recognize similarlipid antigens. For example, a recent report demonstrated thatLPC-specific CD1d-restricted T cells that appeared phenotyp-ically and functionally distinct from NKT cells are expanded inthe blood of many multiple myeloma patients [59]. Thus, thenormal regulatory functions of NKT cells during inflammationmay be overcome in certain pathological conditions by otherCD1d-restricted T cells that have a more harmful impact.

Acknowledgement

This work was funded by NIH grant 1R01AI074940 toJEG.

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