Both CD1d Antigen Presentation and Interleukin-12 Are Required To Activate Natural Killer T Cells during Trypanosoma cruzi Infection
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感染与免疫杂志 2005年第3期
Infectious Disease Research Institute
Department of Pathology, Children's Hospital and Regional Medical Center, Seattle, Washington
ABSTRACT
Mechanisms of natural killer T (NKT)-cell activation remain unclear. Here, we report that during Trypanosoma cruzi infection, interleukin-12 (IL-12) deficiency or anti-CD1d antibody treatment prevents normal activation. The required IL-12 arises independently of MyD88. The data support a model of normal NKT-cell activation that requires IL-12 and TCR stimulation.
TEXT
Detection of liver NKT cells is reduced at day four of T. cruzi infection. Natural killer T (NKT) cells help control infections by Trypanosoma cruzi and other pathogens (5, 9, 10, 13, 28). How NKT cells become activated during these infections remains unclear. Possibilities include T-cell receptor (TCR) stimulation by CD1d presentation of pathogen-derived or self-derived glycolipid antigens or non-TCR stimulation through other NKT-cell receptors, such as the interleukin-12 (IL-12) receptor (2, 4, 11, 18, 29). To explore possible mechanisms of NKT-cell activation during T. cruzi infection, we developed an assay based on NKT-cell activation-induced surface receptor down modulation (14, 31) and our previous observation that during T. cruzi infection NKT cells undergo TCR and NK1.1 down modulation. Initially, we inoculated 7- to 10-week-old wild-type mice (C57BL/6 mice; Charles River, Wilmington, Mass.) with 2 x 105 CL strain T. cruzi trypomastigotes (23, 33) and monitored alterations in liver mononuclear cell TCRs and NK1.1. We found on day four of the infection a reproducible decrease in the number of detectable liver NKT cells and in the intensity of NK1.1 staining (Fig. 1), indicating liver NKT-cell activation.
During T. cruzi infection, IL-12, but not MyD88, is required for normal NKT-cell activation. IL-12 and IL-18 can activate or contribute to NKT-cell activation (6, 11, 20, 21). During infections, these cytokines may arise as a consequence of TLR signaling. In addition, NKT cells express TLR, so it is possible that direct recognition of pathogen-associated molecular patterns leads to NKT-cell activation (25). We analyzed the liver NKT-cell populations of IL-12p40–/– (The Jackson Laboratory, Bar Harbor, Maine) and MyD88–/– mice. MyD88 is an adaptor molecule that is critical for IL-18 signaling and required for many TLR signaling pathways (1, 17, 27). While T. cruzi infection reduced the detectable NKT cells in wild-type and MyD88–/– mice, the number of NKT cells and the intensity of NK1.1 staining did not decline in IL-12–/– mice (Fig. 1). This observation indicates that during T. cruzi infection, IL-12 is required for normal NKT-cell stimulation and receptor down modulation. Furthermore, the data argue that IL-12 can be generated independently of MyD88-dependent TLR signaling. Accordingly, splenocytes placed in ex vivo culture from infected wild-type and infected MyD88–/– mice produced similar amounts of IL-12 (Fig. 2). These data are in agreement with a recent report that demonstrates that during T. cruzi infection, IL-12 is stimulated independently of MyD88 (8). Taken together, our data argue that during T. cruzi infection, IL-12 signals, but neither IL-18 nor MyD88-dependent TLR signals, are required for normal NKT-cell activation.
During T. cruzi infection, CD1d is required for protective NKT-cell activation. We have previously demonstrated that CD1d gene-deficient (CD1d–/–) mice develop greater parasitemia and tissue inflammation than wild-type mice, but since these mice develop without NKT cells, they cannot be used to investigate how NKT cells are activated (9, 10, 26). To investigate if during the infection NKT cells were activated by CD1d antigen presentation, we treated C57BL/6 mice with a blocking anti-CD1d antibody (clone 20H2; American Type Culture Collection, Manassas, Va.) or a control antibody (rat immunoglobulin G; Sigma, St. Louis, Mo.) and then inoculated the mice with T. cruzi (24). On day 4 of the infection, the liver NKT cells of the control antibody-treated mice were decreased in number and in NK1.1 staining intensity, whereas those of the anti-CD1d antibody-treated mice were decreased neither in number nor in NK1.1 staining intensity (Fig. 1). These data argue that CD1d antigen presentation was required for NKT-cell activation and that treatment with anti-CD1d would block protective NKT-cell functions during T. cruzi infection (9, 10). As expected, anti-CD1d antibody-treated mice, compared to control antibody-treated mice, suffered increased infection-induced weight loss and earlier death following a lethal inoculum of T. cruzi (Fig. 3A and B). Furthermore, following a sublethal inoculum, anti-CD1d monoclonal antibody treatment caused increased tissue inflammation (Fig. 3C and D). Together, these data strongly argue that during T. cruzi infection, TCR stimulation by CD1d antigen presentation is required for normal NKT-cell activation and protective functions.
To identify a T. cruzi CD1d-restricted antigen, CD1d-transfected L cells were pulsed with various trypomastigote preparations (live trypomastigotes, dead trypomastigotes, trypomastigote-conditioned media, and trypomastigote lysate) or 100 ng of -galactosylceramide (-GalCer)/ml (as a positive control). After washing, the antigen-pulsed CD1d-transfected L cells (2 x 105) were incubated overnight with a mouse invariant NKT-cell hybridoma (DN32.D3; 5 x 104 cells) (7), and the culture supernatants were assayed for IL-2. -GalCer stimulated IL-2 production, unlike all of the trypomastigote preparations, suggesting that T. cruzi trypomastigotes do not express a CD1d-restricted NKT-cell-specific antigen (data not shown). In support of these in vitro data, the inoculation of mice with dead trypomastigotes did not activate NKT cells in vivo (Fig. 1). Together, these data suggest that during T. cruzi infection, the NKT-cell antigens may be self antigens. Live trypomastigotes might damage host cells and tissues to generate increased amounts of these self antigens.
This study demonstrates that during T. cruzi infection, normal NKT-cell activation requires (i) live T. cruzi inoculation, (ii) IL-12, and (iii) CD1d antigen presentation. The data support a model of NKT-cell activation during infections that requires CD1d presentation of an endogenous self antigen and IL-12 (6). The self antigens might provide weak stimulation that is normally incapable of activating NKT cells without IL-12 (6). These data are consistent with the previous findings that IL-12 enhances NKT-cell activation following exposure to low doses of -GalCer and facilitates NKT-cell activation by self antigens during Salmonella enterica serovar Typhimurium infection (6, 19, 30). IL-12 might cause the antigen-presenting cells to increase expression of costimulatory molecules and thereby facilitate NKT-cell activation (12, 15, 16, 32). Alternatively, analogous to NK cells, IL-12 might act directly on NKT cells by countering inhibitory signals and thus allow activation of the NKT cells (11, 22). In contrast to our data and these studies, a recent report demonstrates that NKT-cell activation during Leishmania donovani infection is triggered by parasite-derived glycolipid antigens independently of IL-12 (3). It remains unclear which antigens stimulate NKT cells during T. cruzi infection. A better understanding of how NKT cells become activated may guide therapies to alleviate infection-induced morbidity and mortality.
ACKNOWLEDGMENTS
We thank Randy Brutkiewicz (Indiana University, Indianapolis) for providing CD1d-transfected L cells and the mouse NKT-cell hybridoma DN32.D3; Charles Scanga and Alan Sher (National Institutes of Health, Bethesda, Md.) for providing MyD88–/– mice (with the permission of Shizou Akira, Osaka University, Osaka, Japan); Yasuhiko Koezuka, Kirin Brewery, Ltd., Gunma, Japan, for providing -GalCer; and Karen Krause, Lori Lager, and Sally Norton at Children's Hospital and Regional Medical Center, Seattle, Washington, for advice and assistance with histological analyses.
This work was supported by National Institutes of Health grant AI49455.
REFERENCES
1. Adachi, O., T. Kawai, K. Takeda, M. Matsumoto, H. Tsutsui, M. Sakagami, K. Nakanishi, and S. Akira. 1998. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9:143-150.
2. Aliberti, J. C., M. A. Cardoso, G. A. Martins, R. T. Gazzinelli, L. Q. Vieira, and J. S. Silva. 1996. Interleukin-12 mediates resistance to Trypanosoma cruzi in mice and is produced by murine macrophages in response to live trypomastigotes. Infect. Immun. 64:1961-1967.
3. Amprey, J. L., J. S. Im, S. J. Turco, H. W. Murray, P. A. Illarionov, G. S. Besra, S. A. Porcelli, and G. F. Spath. 2004. A subset of liver NK T cells is activated during Leishmania donovani infection by CD1d-bound lipophosphoglycan. J. Exp. Med. 200:895-904.
4. Antunez, M. I., and R. L. Cardoni. 2000. IL-12 and IFN-gamma production, and NK cell activity, in acute and chronic experimental Trypanosoma cruzi infections. Immunol. Lett. 71:103-109.
5. Brigl, M., and M. B. Brenner. 2004. CD1: antigen presentation and T cell function. Annu. Rev. Immunol. 22:817-890.
6. Brigl, M., L. Bry, S. C. Kent, J. E. Gumperz, and M. B. Brenner. 2003. Mechanism of CD1d-restricted natural killer T cell activation during microbial infection. Nat. Immunol. 4:1230-1237.
7. Brutkiewicz, R. R., J. R. Bennink, J. W. Yewdell, and A. Bendelac. 1995. TAP-independent, 2-microglobulin-dependent surface expression of functional mouse CD1.1. J. Exp. Med. 182:1913-1919.
8. Campos, M. A., M. Closel, E. P. Valente, J. E. Cardoso, S. Akira, J. I. Alvarez-Leite, C. Ropert, and R. T. Gazzinelli. 2004. Impaired production of proinflammatory cytokines and host resistance to acute infection with Trypanosoma cruzi in mice lacking functional myeloid differentiation factor 88. J. Immunol. 172:1711-1718.
9. Duthie, M. S., M. Kahn, M. White, R. P. Kapur, and S. J. Kahn. 2005. Critical proinflammatory and anti-inflammatory functions of different subsets of CD1d-restricted natural killer T cells during Trypanosoma cruzi infection. Infect. Immun. 73:181-192.
10. Duthie, M. S., M. Wleklinski-Lee, S. Smith, T. Nakayama, M. Taniguchi, and S. J. Kahn. 2002. During Trypanosoma cruzi infection CD1d-restricted NK T cells limit parasitemia and augment the antibody response to a glycophosphoinositol-modified surface protein. Infect. Immun. 70:36-48.
11. Eberl, G., and H. R. MacDonald. 1998. Rapid death and regeneration of NKT cells in anti-CD3- or IL-12-treated mice: a major role for bone marrow in NKT cell homeostasis. Immunity 9:345-353.
12. Falcone, M., F. Facciotti, N. Ghidoli, P. Monti, S. Olivieri, L. Zaccagnino, E. Bonifacio, G. Casorati, F. Sanvito, and N. Sarvetnick. 2004. Up-regulation of CD1d expression restores the immunoregulatory function of NKT cells and prevents autoimmune diabetes in nonobese diabetic mice. J. Immunol. 172:5908-5916.
13. Hansen, D. S., and L. Schofield. 2004. Regulation of immunity and pathogenesis in infectious diseases by CD1d-restricted NKT cells. Int. J. Parasitol. 34:15-25.
14. Harada, M., K. Seino, H. Wakao, S. Sakata, Y. Ishizuka, T. Ito, S. Kojo, T. Nakayama, and M. Taniguchi. 2004. Down-regulation of the invariant V14 antigen receptor in NKT cells upon activation. Int. Immunol. 16:241-247.
15. Hayakawa, Y., K. Takeda, H. Yagita, L. Van Kaer, I. Saiki, and K. Okumura. 2001. Differential regulation of Th1 and Th2 functions of NKT cells by CD28 and CD40 costimulatory pathways. J. Immunol. 166:6012-6018.
16. Ikarashi, Y., R. Mikami, A. Bendelac, M. Terme, N. Chaput, M. Terada, T. Tursz, E. Angevin, F. A. Lemonnier, H. Wakasugi, and L. Zitvogel. 2001. Dendritic cell maturation overrules H-2D-mediated natural killer T (NKT) cell inhibition. Critical role for B7 in CD1d-dependent NKT cell interferon production. J. Exp. Med. 194:1179-1186.
17. Kawai, T., O. Adachi, T. Ogawa, K. Takeda, and S. Akira. 1999. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity 11:115-122.
18. Kawano, T., J. Cui, Y. Koezuka, I. Toura, Y. Kaneko, K. Motoki, H. Ueno, R. Nakagawa, H. Sato, E. Kondo, H. Koseki, and M. Taniguchi. 1997. CD1d-restricted and TCR-mediated activation of V14 NKT cells by glycosylceramides. Science 278:1626-1629.
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22. Ortaldo, J. R., and H. A. Young. 2003. Expression of IFN- upon triggering of activating Ly49D NK receptors in vitro and in vivo: costimulation with IL-12 or IL-18 overrides inhibitory receptors. J. Immunol. 170:1763-1769.
23. Plata, F., F. Garcia-Pons, and H. Eisen. 1984. Antigenic polymorphism of Trypanosoma cruzi: clonal analysis of trypomastigote surface antigens. Eur. J. Immunol. 14:392-399.
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25. Shimizu, H., T. Matsuguchi, Y. Fukuda, I. Nakano, T. Hayakawa, O. Takeuchi, S. Akira, M. Umemura, T. Suda, and Y. Yoshikai. 2002. Toll-like receptor 2 contributes to liver injury by Salmonella infection through Fas ligand expression on NKT cells in mice. Gastroenterology 123:1265-1277.
26. Smiley, S. T., M. H. Kaplan, and M. J. Grusby. 1997. Immunoglobulin E production in the absence of interleukin-4-secreting CD1-dependent cells. Science 275:977-979.
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28. Taniguchi, M., M. Harada, S. Kojo, T. Nakayama, and H. Wakao. 2003. The regulatory role of V14 NKT cells in innate and acquired immune response. Annu. Rev. Immunol. 21:483-513.
29. Taniguchi, M., and T. Nakayama. 2000. Recognition and function of V14 NKT cells. Semin. Immunol. 12:543-550.
30. Trobonjaca, Z., F. Leithauser, P. Moller, R. Schirmbeck, and J. Reimann. 2001. Activating immunity in the liver. I. Liver dendritic cells (but not hepatocytes) are potent activators of IFN- release by liver NKT cells. J. Immunol. 167:1413-1422.
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Department of Pathology, Children's Hospital and Regional Medical Center, Seattle, Washington
ABSTRACT
Mechanisms of natural killer T (NKT)-cell activation remain unclear. Here, we report that during Trypanosoma cruzi infection, interleukin-12 (IL-12) deficiency or anti-CD1d antibody treatment prevents normal activation. The required IL-12 arises independently of MyD88. The data support a model of normal NKT-cell activation that requires IL-12 and TCR stimulation.
TEXT
Detection of liver NKT cells is reduced at day four of T. cruzi infection. Natural killer T (NKT) cells help control infections by Trypanosoma cruzi and other pathogens (5, 9, 10, 13, 28). How NKT cells become activated during these infections remains unclear. Possibilities include T-cell receptor (TCR) stimulation by CD1d presentation of pathogen-derived or self-derived glycolipid antigens or non-TCR stimulation through other NKT-cell receptors, such as the interleukin-12 (IL-12) receptor (2, 4, 11, 18, 29). To explore possible mechanisms of NKT-cell activation during T. cruzi infection, we developed an assay based on NKT-cell activation-induced surface receptor down modulation (14, 31) and our previous observation that during T. cruzi infection NKT cells undergo TCR and NK1.1 down modulation. Initially, we inoculated 7- to 10-week-old wild-type mice (C57BL/6 mice; Charles River, Wilmington, Mass.) with 2 x 105 CL strain T. cruzi trypomastigotes (23, 33) and monitored alterations in liver mononuclear cell TCRs and NK1.1. We found on day four of the infection a reproducible decrease in the number of detectable liver NKT cells and in the intensity of NK1.1 staining (Fig. 1), indicating liver NKT-cell activation.
During T. cruzi infection, IL-12, but not MyD88, is required for normal NKT-cell activation. IL-12 and IL-18 can activate or contribute to NKT-cell activation (6, 11, 20, 21). During infections, these cytokines may arise as a consequence of TLR signaling. In addition, NKT cells express TLR, so it is possible that direct recognition of pathogen-associated molecular patterns leads to NKT-cell activation (25). We analyzed the liver NKT-cell populations of IL-12p40–/– (The Jackson Laboratory, Bar Harbor, Maine) and MyD88–/– mice. MyD88 is an adaptor molecule that is critical for IL-18 signaling and required for many TLR signaling pathways (1, 17, 27). While T. cruzi infection reduced the detectable NKT cells in wild-type and MyD88–/– mice, the number of NKT cells and the intensity of NK1.1 staining did not decline in IL-12–/– mice (Fig. 1). This observation indicates that during T. cruzi infection, IL-12 is required for normal NKT-cell stimulation and receptor down modulation. Furthermore, the data argue that IL-12 can be generated independently of MyD88-dependent TLR signaling. Accordingly, splenocytes placed in ex vivo culture from infected wild-type and infected MyD88–/– mice produced similar amounts of IL-12 (Fig. 2). These data are in agreement with a recent report that demonstrates that during T. cruzi infection, IL-12 is stimulated independently of MyD88 (8). Taken together, our data argue that during T. cruzi infection, IL-12 signals, but neither IL-18 nor MyD88-dependent TLR signals, are required for normal NKT-cell activation.
During T. cruzi infection, CD1d is required for protective NKT-cell activation. We have previously demonstrated that CD1d gene-deficient (CD1d–/–) mice develop greater parasitemia and tissue inflammation than wild-type mice, but since these mice develop without NKT cells, they cannot be used to investigate how NKT cells are activated (9, 10, 26). To investigate if during the infection NKT cells were activated by CD1d antigen presentation, we treated C57BL/6 mice with a blocking anti-CD1d antibody (clone 20H2; American Type Culture Collection, Manassas, Va.) or a control antibody (rat immunoglobulin G; Sigma, St. Louis, Mo.) and then inoculated the mice with T. cruzi (24). On day 4 of the infection, the liver NKT cells of the control antibody-treated mice were decreased in number and in NK1.1 staining intensity, whereas those of the anti-CD1d antibody-treated mice were decreased neither in number nor in NK1.1 staining intensity (Fig. 1). These data argue that CD1d antigen presentation was required for NKT-cell activation and that treatment with anti-CD1d would block protective NKT-cell functions during T. cruzi infection (9, 10). As expected, anti-CD1d antibody-treated mice, compared to control antibody-treated mice, suffered increased infection-induced weight loss and earlier death following a lethal inoculum of T. cruzi (Fig. 3A and B). Furthermore, following a sublethal inoculum, anti-CD1d monoclonal antibody treatment caused increased tissue inflammation (Fig. 3C and D). Together, these data strongly argue that during T. cruzi infection, TCR stimulation by CD1d antigen presentation is required for normal NKT-cell activation and protective functions.
To identify a T. cruzi CD1d-restricted antigen, CD1d-transfected L cells were pulsed with various trypomastigote preparations (live trypomastigotes, dead trypomastigotes, trypomastigote-conditioned media, and trypomastigote lysate) or 100 ng of -galactosylceramide (-GalCer)/ml (as a positive control). After washing, the antigen-pulsed CD1d-transfected L cells (2 x 105) were incubated overnight with a mouse invariant NKT-cell hybridoma (DN32.D3; 5 x 104 cells) (7), and the culture supernatants were assayed for IL-2. -GalCer stimulated IL-2 production, unlike all of the trypomastigote preparations, suggesting that T. cruzi trypomastigotes do not express a CD1d-restricted NKT-cell-specific antigen (data not shown). In support of these in vitro data, the inoculation of mice with dead trypomastigotes did not activate NKT cells in vivo (Fig. 1). Together, these data suggest that during T. cruzi infection, the NKT-cell antigens may be self antigens. Live trypomastigotes might damage host cells and tissues to generate increased amounts of these self antigens.
This study demonstrates that during T. cruzi infection, normal NKT-cell activation requires (i) live T. cruzi inoculation, (ii) IL-12, and (iii) CD1d antigen presentation. The data support a model of NKT-cell activation during infections that requires CD1d presentation of an endogenous self antigen and IL-12 (6). The self antigens might provide weak stimulation that is normally incapable of activating NKT cells without IL-12 (6). These data are consistent with the previous findings that IL-12 enhances NKT-cell activation following exposure to low doses of -GalCer and facilitates NKT-cell activation by self antigens during Salmonella enterica serovar Typhimurium infection (6, 19, 30). IL-12 might cause the antigen-presenting cells to increase expression of costimulatory molecules and thereby facilitate NKT-cell activation (12, 15, 16, 32). Alternatively, analogous to NK cells, IL-12 might act directly on NKT cells by countering inhibitory signals and thus allow activation of the NKT cells (11, 22). In contrast to our data and these studies, a recent report demonstrates that NKT-cell activation during Leishmania donovani infection is triggered by parasite-derived glycolipid antigens independently of IL-12 (3). It remains unclear which antigens stimulate NKT cells during T. cruzi infection. A better understanding of how NKT cells become activated may guide therapies to alleviate infection-induced morbidity and mortality.
ACKNOWLEDGMENTS
We thank Randy Brutkiewicz (Indiana University, Indianapolis) for providing CD1d-transfected L cells and the mouse NKT-cell hybridoma DN32.D3; Charles Scanga and Alan Sher (National Institutes of Health, Bethesda, Md.) for providing MyD88–/– mice (with the permission of Shizou Akira, Osaka University, Osaka, Japan); Yasuhiko Koezuka, Kirin Brewery, Ltd., Gunma, Japan, for providing -GalCer; and Karen Krause, Lori Lager, and Sally Norton at Children's Hospital and Regional Medical Center, Seattle, Washington, for advice and assistance with histological analyses.
This work was supported by National Institutes of Health grant AI49455.
REFERENCES
1. Adachi, O., T. Kawai, K. Takeda, M. Matsumoto, H. Tsutsui, M. Sakagami, K. Nakanishi, and S. Akira. 1998. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 9:143-150.
2. Aliberti, J. C., M. A. Cardoso, G. A. Martins, R. T. Gazzinelli, L. Q. Vieira, and J. S. Silva. 1996. Interleukin-12 mediates resistance to Trypanosoma cruzi in mice and is produced by murine macrophages in response to live trypomastigotes. Infect. Immun. 64:1961-1967.
3. Amprey, J. L., J. S. Im, S. J. Turco, H. W. Murray, P. A. Illarionov, G. S. Besra, S. A. Porcelli, and G. F. Spath. 2004. A subset of liver NK T cells is activated during Leishmania donovani infection by CD1d-bound lipophosphoglycan. J. Exp. Med. 200:895-904.
4. Antunez, M. I., and R. L. Cardoni. 2000. IL-12 and IFN-gamma production, and NK cell activity, in acute and chronic experimental Trypanosoma cruzi infections. Immunol. Lett. 71:103-109.
5. Brigl, M., and M. B. Brenner. 2004. CD1: antigen presentation and T cell function. Annu. Rev. Immunol. 22:817-890.
6. Brigl, M., L. Bry, S. C. Kent, J. E. Gumperz, and M. B. Brenner. 2003. Mechanism of CD1d-restricted natural killer T cell activation during microbial infection. Nat. Immunol. 4:1230-1237.
7. Brutkiewicz, R. R., J. R. Bennink, J. W. Yewdell, and A. Bendelac. 1995. TAP-independent, 2-microglobulin-dependent surface expression of functional mouse CD1.1. J. Exp. Med. 182:1913-1919.
8. Campos, M. A., M. Closel, E. P. Valente, J. E. Cardoso, S. Akira, J. I. Alvarez-Leite, C. Ropert, and R. T. Gazzinelli. 2004. Impaired production of proinflammatory cytokines and host resistance to acute infection with Trypanosoma cruzi in mice lacking functional myeloid differentiation factor 88. J. Immunol. 172:1711-1718.
9. Duthie, M. S., M. Kahn, M. White, R. P. Kapur, and S. J. Kahn. 2005. Critical proinflammatory and anti-inflammatory functions of different subsets of CD1d-restricted natural killer T cells during Trypanosoma cruzi infection. Infect. Immun. 73:181-192.
10. Duthie, M. S., M. Wleklinski-Lee, S. Smith, T. Nakayama, M. Taniguchi, and S. J. Kahn. 2002. During Trypanosoma cruzi infection CD1d-restricted NK T cells limit parasitemia and augment the antibody response to a glycophosphoinositol-modified surface protein. Infect. Immun. 70:36-48.
11. Eberl, G., and H. R. MacDonald. 1998. Rapid death and regeneration of NKT cells in anti-CD3- or IL-12-treated mice: a major role for bone marrow in NKT cell homeostasis. Immunity 9:345-353.
12. Falcone, M., F. Facciotti, N. Ghidoli, P. Monti, S. Olivieri, L. Zaccagnino, E. Bonifacio, G. Casorati, F. Sanvito, and N. Sarvetnick. 2004. Up-regulation of CD1d expression restores the immunoregulatory function of NKT cells and prevents autoimmune diabetes in nonobese diabetic mice. J. Immunol. 172:5908-5916.
13. Hansen, D. S., and L. Schofield. 2004. Regulation of immunity and pathogenesis in infectious diseases by CD1d-restricted NKT cells. Int. J. Parasitol. 34:15-25.
14. Harada, M., K. Seino, H. Wakao, S. Sakata, Y. Ishizuka, T. Ito, S. Kojo, T. Nakayama, and M. Taniguchi. 2004. Down-regulation of the invariant V14 antigen receptor in NKT cells upon activation. Int. Immunol. 16:241-247.
15. Hayakawa, Y., K. Takeda, H. Yagita, L. Van Kaer, I. Saiki, and K. Okumura. 2001. Differential regulation of Th1 and Th2 functions of NKT cells by CD28 and CD40 costimulatory pathways. J. Immunol. 166:6012-6018.
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