ANRV306-IY25-12 ARI 11 February 2007 12:20 pathogen and member of the Rickettsiales that is of widespread significance for mammals, including wild and domesticated ruminants, dogs, and humans from some regions of the world such as Africa and East Asia. Ehrlichia muris activates NKT cells independently of iGb3, and its clearance was profoundly altered in CD1d- or Jα18-deficient animals (23). Ehrlichia is a Gram-negative, LPS-negative obligate intracellular bacterium, whose cell wall composition has not been elucidated. Interestingly, many other bacteria, particu- larly the Gram-negative, LPS-positive ones, can activate NKT cells. However, rather than provide their own NKT ligands like Sphin- gomonas or Ehrlichia, these bacteria appear to trigger autoreactive NKT cell responses (23, 60). In the case of Salmonella, this is suggested by the abrogation of NKT cell activation in the presence of DCs lacking β-hexosaminidase B, the enzyme responsible for the generation of iGb3 from iGb4 in the lysosome, and by blocking experiments with the lectin Griffonia simplicifolia IB4, which recognizes the terminal sugar of the Galα1- 3Gal epitope of iGb3 bound to CD1d and blocks NKT cell activation (23). Strikingly, NKT cell activation by Gram-negative, LPS- positive Salmonella is absolutely dependent upon TLR signaling through the adaptors MyD88 and Trif, and upon IL-12 release by the APC, although the precise TLR combi- nation and the corresponding microbial struc- tures involvedremainto bedetermined. Thus, the proposed scenario suggests that TLR sig- naling leading, butnot limited, to IL-12secre- tion enhances the ability of DCs to stimulate NKT cells through presentation of endoge- nous ligands (Figure 7). Whether TLR signaling induces an up- regulation of iGb3 or changes in the expres- sion of other factors such as, for example, NK receptor ligands is unclear. Contrary to an early report (195), NKT cells do not usually Late endosome/lysosome TLR4 Bacterial Ag iGb3 IL-12p40 Direct microbial recognition Indirect microbial recognition LPS Gram-negative, LPS-negative bacteria Gram-negative bacteria ? NKT cell iGb3 Bacterial Ag Figure 7 Dual recognition of self and microbial glycosphingolipids during microbial infections. On the left, infection by Gram-negative, LPS-negative Sphingomonas induces direct activation of NKT cells through recognition of microbial cell wall α-glycuronylceramide. On the right, infection by Gram-negative, LPS-positive Salmonella activates TLR4 through LPS and induces IL-12, revealing constitutive autoreactive recognition of iGb3 through the secretion of IFN-γ (indirect microbial recognition). www.annualreviews.org • Biology of NKT Cells 317 Annu. Rev. Immunol. 2007.25:297-336. Downloaded from arjournals.annualreviews.org by HINARI on 09/21/07. For personal use only. ANRV306-IY25-12 ARI 11 February 2007 12:20 constitute the predominant cell type that pro- duces IFN-γ in response to IL-12 in vivo (60, 196). This explains why they generally do not appear to be essential in fighting Gram-negative, LPS-positive bacteria. How- ever, an impact on bacterial clearance has been observed in the case of lung infection with Pseudomonas aeruginosa, where CD1d- deficient mice exhibited a ∼20-fold increased bacterial count in the lung within 6–24 h postinoculation and an approximately three- fold decrease in MIP-2 and neutrophils in the bronchoalveolar lavage (197). This may not be the case at other sites of infection (198). Variations have been noted as well in reports assessing the role of NKT cells versus NK cells in LPS-induced toxic shock in vivo (199, 200). Primary Biliary Cirrhosis and Sphingomonas An intriguing connection between primary biliary cirrhosis (PBC), Sphingomonas, and NKT cells has emerged recently. PBC is a disease characterized by the presence of an- timitochondrial antibodies, liver lymphocytic infiltrates, and the chronic destruction of the biliary epithelium, which leads to cirrhosis (201). Interestingly, the autoantibodies recog- nize an epitope of the mitochondrial PDC- E2 enzyme that is particularly well conserved in Novosphingobium aromaticivorans, a strain of Sphingomonas. Furthermore, PBC patients, including those lacking antimitochondrial an- tibodies, were specifically seropositive against Sphingomonas, which was detected by PCR in stool samples of 25% of diseased or healthy individuals, suggesting that PBC may be in- duced by aberrant host reactivity to this bac- terium (202). PBC patients also showed an en- richment of Vα24 NKT cells in liver biopsies, but a depletion in blood (203). In light of the recent finding that Sphingomonas cell wall gly- colipids specifically activate NKT cells, these studies suggest that NKT cells may play a key role in the pathogeny of PBC by promoting aberrant responses to Sphingomonas. Parasitic Infections Shofield and colleagues (204) suggested that the production of IgG antibodies to the malaria circumsporozoite antigen, a key com- ponent of protective immune responses in humans, depended on NKT cell recogni- tion of malarial glycosylphosphatidylinosi- tol antigens in a mouse model. However, additional experiments failed to detect a CD1d-dependent component tothis antibody response, and glycosylphosphatidylinositols have not been identified as NKT cell anti- gens in other reports (205, 206). In the con- text of helminth infection, DCs pulsed with Schistosoma mansoni eggs activated NKT cells to secrete Th1 and Th2 cytokines in vitro in a β-hexosaminidase-B-dependent but MyD88- independent manner, suggesting recognition of the self ligand iGb3 in the absence of TLR signaling (207). Viral Infections Relatively modest defects in the clearance of some viruses have been reported in CD1d- deficient mice infected with encephalomy- ocarditis virus (208) or coxsackie B3 (209), but these defects were not observed in Jα18- deficient mice, ruling out a specific role of Vα14 NKT cells. Infections with lym- phocytic choriomeningitis virus, mouse cy- tomegalovirus, vaccinia virus, andcoronavirus were unaffected. Studies in humans have sug- gested a profibrotic role of Vα24 NKT cells in hepatitis C (85) and the accumulation of non-Vα24 CD1d-restricted T cells (210). Al- though a specific role of Vα14 NKT cells in HSV infection remains controversial (211, 212), recent studies have suggested that vi- ral invasion may be associated with counter- measures against CD1d or NKT cells. For example, HSV-1 drastically and specifically impaired CD1d recycling from the lysosome to the plasma membrane, an essential pathway for glycolipid antigen presentation to NKT cells (96). Kaposi sarcoma–associated herpes virus encodes two modulators of immune 318 Bendelac · Savage · Teyton Annu. Rev. Immunol. 2007.25:297-336. Downloaded from arjournals.annualreviews.org by HINARI on 09/21/07. For personal use only. ANRV306-IY25-12 ARI 11 February 2007 12:20 recognition, MIR1 and MIR2, that downreg- ulated CD1d in addition to other immunolog- ically relevant molecules such as MHC class I, CD86, and intracellular adhesion molecule (ICAM)-1 through ubiquitination of lysine residues in their cytoplasmic tail (95). The lethal outcome of infections with Epstein- Barr virus in patients with X-linked lympho- proliferative (XLP) immunodeficiency syn- drome due to SAP mutations was hypothe- sized to result from the absence of NKT cells (144). Which of these effects or associations reflect a specific viral evasion/immune defense strategy and the nature of the NKT ligandsin- volved in these infectious conditions remain to be determined. NKT Cells in Noninfectious Diseases A role of NKT cells has been suggested in a wide variety of disease conditions. At present, however, many reports, lacking a detailed mechanistic understanding, remain isolated or are based merely on the analysis of NKT cell–deficient mice. Rather than compiling an exhaustive list of the published claims, this re- view provides a critical appraisal of selected reports carrying important conceptual or clin- ical implications. One frequently overlooked but recurrent methodological issue inherent in the use of CD1d- or Jα18-deficient mice is the extent to which gene-deficient mice are matched with littermate controls with re- spect to genetic background and environmen- tal factors. This is particularly important in studies of complex multigenetic diseases such as diabetes, lupus, cancer, or asthma. In ad- dition, the injection of αGalCer as a gain- of-function experiment should be interpreted with caution because the massive release of cy- tokines induced by this procedure is unlikely to model chronic diseases. It may not be sur- prising, therefore, that some claims have be- come controversial or will need to be rein- terpreted, complicating the task of drawing a clear picture of the involvement of NKT cells in noninfectious diseases. Type I diabetes. The relative deficiency of NKT cells in NOD mice (36, 37), combined with the notion that these cells represent a po- tent source of Th2 cytokines, prompted the original speculation of a causal relationship with diabetes. Early claims that humans with type I diabetes exhibited severe NKT cell de- fects and that their sera had less IL-4 than controls (213, 214) were not confirmed when more specific methodologiesbecame available (38, 215). Researchers interpreted reports of aggravated disease in CD1d-deficient NOD mice (216, 217) as suggesting that, although defective, the residual NKT cells in NOD mice still suppressed autoimmunity. How- ever, independent studies in different colonies of CD1d-deficient and Jα18-deficient mice failed to support these claims (218), and par- tial reconstitution of NKT cells in NOD mice carrying the B6 Nkt1 locus did not pro- tect against diabetes (34). Transgenic expres- sion of the Vα14-Jα18 TCRα chain in NOD mice prevented diabetes, but this could be explained by the reduced frequency of islet- specific T cells and the general Th2 bias of these mice (219). Likewise, the suppression of diabetes by αGalCer multi-injection regi- mens could be the mere consequence of mas- sive cytokine release (220, 221). More di- rect transfer experiments using diabetogenic T cells and NKT cells have suggested sup- pressive or enhancing roles of NKT cells in different experimental systems (222, 223). Although other more circumstantial studies have suggested a role of NKT cells in this disease, it seems reasonable to conclude at this point that there is no decisive evidence for a substantial or specific role of NKT cells in mouse or human type I diabetes. Lupus. Hyperreactive NKT cells were shown to accumulate in aging NZB/W mice (224) and suggested to help B cells produce anti-DNA antibodies (225). However, studies of CD1d-deficient lupus-prone mice have not yielded concordant results (226–228), and injections of αGalCer ameliorated or www.annualreviews.org • Biology of NKT Cells 319 Annu. Rev. Immunol. 2007.25:297-336. Downloaded from arjournals.annualreviews.org by HINARI on 09/21/07. For personal use only. ANRV306-IY25-12 ARI 11 February 2007 12:20 aggravated disease, depending on the mouse strain (229). Cancer. Similar to the general immune sup- pression of T cells commonly encountered in cancerous states, NKT cells were decreased or functionally hyporeactive in cancer-bearing mice and humans (230, 231). One tumor shed glycosphingolipids thatcould inhibit thestim- ulation of NKT cells in vitro (232). How- ever, multiple mechanisms are likely to con- tribute to the deficiency of both T and NKT cells. In one report, the frequency of sarcomas six months after intramuscular injection of the chemical carcinogen methylcholantrene (MCA) decreased two- to threefold in Jα18 knockout NKT cell–deficient mice (233). This observation, which suggested that NKT cells, similar to γδ T cells and NK cells, may be agents of immune surveillance against pri- mary cancers has remained isolated. In a tumor transplant model, subcutaneous injection of a fibrosarcoma tumor line derived from MCA-inoculated Jα18-deficient mice produced tumors that grew faster in Jα18- deficient compared with wild-type mice and were prevented by transfers of purified NKT cells into Jα18-deficient hosts (234). CD1d expression and the presence of CD8 T cells in the host were required for tumor rejection, implying ligand recognition on host-derived cells, presumably APCs, rather than on tu- mor cells. The nature of the tumor-associated NKT ligands has not been identified. These experiments also revealed a specialized func- tion of liver DN—as compared with CD4— NKT cells in this Th1-mediated response (128). In apparent contrast with this fibrosar- coma model, CD1d-deficient mice controlled the growth of otherwise relapsing subcuta- neous transplants of the 15-12RM tumor line, suggesting that a natural CD1d-dependent mechanism suppressed tumor rejection (235). Further studies dissected a complex cellu- lar network that involved IL-13-producing CD1d-restricted CD4 suppressors interact- ing with TGF-β-producing myeloid cells to suppress antitumor CTL responses. Because Jα18-deficient mice did not share the pheno- type of CD1d-deficient mice, the study con- cluded that other less well-known types of CD1d-restricted T cells might be involved (236). As in the MCA-induced tumor trans- plants, these tumors did not express CD1d, yet CD1dexpression by host cells, presumably APCs, was required to observe the NKT cell effects. In contrast, the growth of the CD1d- transfected RMA/S tumor cell line cells was inhibited by Vα14 NKT cells (237). In con- clusion, the notion that mVα14 and hVα24 NKT cells regulate cancer rejection is based largely on tumor transplant models, and the relevance to natural clinical conditions re- mains to be determined. Asthma. CD1d- and Jα18-deficient mice were reported to exhibit decreased allergen- induced airway hyperreactivity in the alum- ovalbumin model of asthma, where mice are intraperitoneally sensitized with ovalbumin mixed in alum and subsequently challenged with ovalbumin inhalation (238, 239). How- ever, similar studies in another laboratory have failed to observe differences between CD1d-deficient and wild-type mice (R. Lock- sley, personal communication). In humans with persistent, moderate-to-severe asthma, Vα24 NKT cells dominated the bronchial Th2 infiltrate (240). The extent of this NKT cell expansion has been disputed, however, perhaps reflecting differences in the cohorts of asthma patients examined or the methods for identifying NKT cells (241). Atherosclerosis. CD1d deficiency de- creased the level of atherosclerosis in apoE- or LDL receptor–deficient mice, although the effects observed were only mild and transient in some studies (241, 242). Other disease conditions. Additional ob- servations suggesting a suppressive role of NKT cells in some models of delayed- type hypersensitivity (242, 243), in anterior 320 Bendelac · Savage · Teyton Annu. Rev. Immunol. 2007.25:297-336. Downloaded from arjournals.annualreviews.org by HINARI on 09/21/07. For personal use only. ANRV306-IY25-12 ARI 11 February 2007 12:20 chamber–associated immune deviation (244), and in burn injury (245) have been reported. In summary, contrasting with numerous reports suggesting a contribution of NKT cells in a range of noninfectious diseases, a convincing picture has not yet emerged as to the strength or consistency of the observed effects, their mechanisms, or their relevance to physiological or clinical conditions. Future experiments are needed to define those dis- eases and conditions that are regulated specif- ically by mVα14 or hVα24 NKT cells and to dissect the mechanisms involved. THE LARGER CD1 UNIVERSE Although T cells recognizing lipids pre- sented by other CD1 isotypes were the first discovered (44), their study now represents only a small fraction of the current in- vestigations on CD1-mediated antigen pre- sentation, which focus overwhelmingly on the CD1d/NKT cell system. CD1d is the only representative in mouse and rat of a larger family of β2-microglobulin-associated MHC-like molecules that, in other mam- malian species, comprises CD1a, -b, and -c, as well as CD1e (44). CD1 and MHC are en- coded in different loci, but recent genomic studies in chicken suggest that they originated from the same primordial MHC locus (246). CD1a, -b, and -c differ in their location in different endosomal compartments, in early recycling to late endosome and lysosome, and also in the architecture of their lipid-binding grooves, which suggests that each is special- ized to capture different lipids in different en- dosomal compartments (44). Individual self and microbial lipid-specific T cell clones have been derived in vitro in humans, but relatively little is known about the T cell types and TCR repertoires associated with CD1a, -b, and -c and about their function in the human system. With respect to CD1d, however, it is well established that the major population of CD1d-restricted T cells in mouse is the NKT cell population that expresses semi-invariant TCRs, predominantly Vα14-Jα18, and per- forms innate-like functions (19). The pres- ence of a more diverse population has been suggested recently, more convincingly in hu- mans, indicating that an adaptive population of lipid-specific CD1d-restricted T cells may be available (210, 247, 248). The biology of these cells remains largely unexplored, and fu- ture studies in this area would resolve a fasci- nating and long-standing debate in the field of T cell recognition. Indeed, glycolipids are not easily mutated or modified, and although the potential theoretical combinations of car- bohydrates are extremely diverse, the universe of microbial glycolipidsis limited owing toen- zyme specificity for both donor and acceptor substrates in glycolipid synthesis. Thus, the glycolipid-specific repertoire did not evolve under the same pressure that operated on the peptide-specific repertoire, where single mu- tations produce new T cell epitopes. How diverse and specific this glycolipid-specific repertoire may be is an important question for future research because conserved glycol- ipids may represent ideal, fixed targets for vaccine development. In addition, how cross- reactive the MHC- and CD1-restricted TCR repertoires are is a fundamental issue that remains to be investigated. Given that the groove of CD1 molecules is significantly nar- rower than that of MHC proteins and that at least a proportion of the TCR repertoire ap- pears to be intrinsically MHC-restricted (249, 250), one would assume that the peptide- specific and glycolipid-specific TCR reper- toire should be essentially non-cross-reactive, a prediction that remains to be tested. SUMMARY Recent studies have elucidated novel and striking aspects of NKT cell development and of the cell and structural biology of lipid antigen processing and recognition. Key candidate antigens have been identified that provide a framework for understanding the evolution and function of this innate-like lin- eage, particularly in microbial infections. Fu- ture work will clarify the range and nature www.annualreviews.org • Biology of NKT Cells 321 Annu. Rev. Immunol. 2007.25:297-336. Downloaded from arjournals.annualreviews.org by HINARI on 09/21/07. For personal use only. ANRV306-IY25-12 ARI 11 February 2007 12:20 of the most physiologically relevant ligands and the structural basis of their recognition by the semi-invariant TCRs. These solid ad- vances in fundamental biology should help develop a mechanistic understanding of the broad and sometimes controversial array of diseases in which NKT cells are increasingly implicated. ACKNOWLEDGMENTS We thank past and present members of our laboratories for their contributions to the un- derstanding of NKT cell biology; Seth Scanlon and Omita Trivedi, for help with the figures; and Richard Locksley, Diane Mathis, and Thomas Blankenstein for sharing unpublished re- sults. Dirk Zajonc generated the structural representation in Figure 2. This work is supported by the Howard Hughes Medical Institute (A.B.) and by a program project grant from the National Institutes of Health (A.B., P.B.S., L.T.). No review on NKT cell biology can ade- quately describe every interesting paper, and we apologize to those investigators whose work could not be cited because of space limitations. LITERATURE CITED 1. Sumida T, Takei I, Taniguchi M. 1984. Activation of acceptor-suppressor hybridoma with antigen specific suppressor T cell factor of two-chain type: requirement of the antigen- and the I-J-restricting specificity. J. Immunol. 133:1131–36 2. Sumida T, Taniguchi M. 1985. 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