Abstract
There are many mechanisms that regulate and dampen the immune response to cancers, including several types of regulatory T cells. Besides the T reg cell, we have identified another immunoregulatory circuit initiated by NKT cells that produce IL-13 in response to tumor growth and this IL-13 then induces myeloid cells to make TGF-β that inhibits cytotoxic T cell-mediated tumor immunosurveillance in several mouse tumor models. This finding created a paradox in the role of NKT cells in tumor immunity, in that they can also contribute to protection. We resolve this paradox by the finding that the suppressive NKT cell is a type II NKT cell that lacks the canonical invariant T cell receptor, whereas the protective cell is a type I NKT cell that expresses the invariant receptor. Further, we see that these two subsets of NKT cells counter-regulate each other, defining a new immunoregulatory axis. The balance along this axis may determine the outcome of tumor immunosurveillance as well as influence the efficacy of anti-cancer vaccines and immunotherapy.
Similar content being viewed by others
References
Akbari O, Stock P, DeKruyff RH, Umetsu DT (2003) Role of regulatory T cells in allergy and asthma. Curr Opin Immunol 15:627
Ambrosino E, Terabe M, Halder RC, Peng J, Takaku S, Miyake S, Yamamura T, Kumer V, Berzofsky JA (2007) Cross-regulation between type I and type II NKT cells in regulating tumor immunity: a new immunoregulatory axis. J Immunol 179:5126
Bendelac A, Savage PB, Teyton L (2007) The biology of NKT cells. Annu Rev Immunol 25:297
Brutkiewicz RR (2006) CD1d ligands: the good, the bad, and the ugly. J Immunol 177:769
Crowe NY, Smyth MJ, Godfrey DI (2002) A critical role for natural killer T cells in immunosurveillance of methylcholanthrene-induced sarcomas. J Exp Med 196:119
Crowe NY, Coquet JM, Berzins SP, Kyparissoudis K, Keating R, Pellicci DG, Hayakawa Y, Godfrey DI, Smyth MJ (2005) Differential antitumor immunity mediated by NKT cell subsets in vivo. J Exp Med 202:1279
Cui J, Shin T, Kawano T, Sato H, Kondo E, Toura I, Kaneko Y, Koseki H, Kanno M, Taniguchi M (1997) Requirement for Valpha14 NKT cells in IL-12-mediated rejection of tumors. Science 278:1623
Godfrey DI, MacDonald HR, Kronenberg M, Smyth MJ, Van Kaer L (2004) NKT cells: what’s in a name? Nat Rev Immunol 4:231
Gumperz JE, Roy C, Makowska A, Lum D, Sugita M, Podrebarac T, Koezuka Y, Porcelli SA, Cardell S, Brenner MB, Behar SM (2000) Murine CD1d-restricted T cell recognition of cellular lipids. Immunity 12:211
Jahng A, Maricic I, Aguilera C, Cardell S, Halder RC, Kumar V (2004) Prevention of Autoimmunity by Targeting a Distinct, Noninvariant CD1d-reactive T Cell Population Reactive to Sulfatide. J Exp Med 199:947
Kawano T, Cui J, Koezuka Y, Toura I, Kaneko Y, Motoki K, Ueno H, Nakagawa R, Sato H, Kondo E, Koseki H, Taniguchi M (1997) CD1d-restricted and TCR-mediated activation of valpha14 NKT cells by glycosylceramides. Science 278:1626
Kronenberg M (2005) Toward an understanding of NKT cell biology: progress and paradoxes. Annu Rev Immunol 23:877
Matsui S, Ahlers JD, Vortmeyer AO, Terabe M, Tsukui T, Carbone DP, Liotta LA, Berzofsky J (1999) A model for CD8+ CTL tumor immunosurveillance and regulation of tumor escape by CD4 T cells through an effect on quality of CTL. J Immunol 163:184
Meyer EH, Goya S, Akbari O, Berry GJ, Savage PB, Kronenberg M, Nakayama T, DeKruyff RH, Umetsu DT (2006) Glycolipid activation of invariant T cell receptor+ NK T cells is sufficient to induce airway hyperreactivity independent of conventional CD4+ T cells. Proc Natl Acad Sci USA 103:2782
Oki S, Chiba A, Yamamura T, Miyake S (2004) The clinical implication and molecular mechanism of preferential IL-4 production by modified glycolipid-stimulated NKT cells. J Clin Invest 113:1631
Onizuka S, Tawara I, Shimizu J, Sakaguchi S, Fujita T, Nakayama E (1999) Tumor rejection by in vivo administration of anti-CD25 (interleukin-2 receptor alpha) monoclonal antibody. Cancer Res 59:3128
Park JM, Terabe M, van den Broeke LT, Donaldson DD, Berzofsky JA (2004) Unmasking immunosurveillance against a syngeneic colon cancer by elimination of CD4+ NKT regulatory cells and IL-13. Int J Cancer 114:80
Roberts DD (1986) Sulfatide-binding proteins. Chem Phys Lipids 42:173
Shimizu J, Yamazaki S, Sakaguchi S (1999) Induction of tumor immunity by removing CD25+ CD4+ T cells: a common basis between tumor immunity and autoimmunity. J Immunol 163:5211
Sidobre S, Hammond KJ, Benazet-Sidobre L, Maltsev SD, Richardson SK, Ndonye RM, Howell AR, Sakai T, Besra GS, Porcelli SA, Kronenberg M (2004) The T cell antigen receptor expressed by Valpha14i NKT cells has a unique mode of glycosphingolipid antigen recognition. Proc Natl Acad Sci USA 101:12254
Smyth MJ, Thia KY, Street SE, Cretney E, Trapani JA, Taniguchi M, Kawano T, Pelikan SB, Crowe NY, Godfrey DI (2000) Differential tumor surveillance by natural killer (NK) and NKT cells. J Exp Med 191:661
Terabe M, Matsui S, Noben-Trauth N, Chen H, Watson C, Donaldson DD, Carbone DP, Paul WE, Berzofsky JA (2000) NKT cell-mediated repression of tumor immunosurveillance by IL-13 and the IL-4R-STAT6 pathway. Nat Immunol 1:515
Terabe M, Berzofsky JA (2007) NKT cells in immunoregulation of tumor immunity: cross-regulation between two subsets. Trends Immunol 28:491
Terabe M, Matsui S, Park J-M, Mamura M, Noben-Trauth N, Donaldson DD, Chen W, Wahl SM, Ledbetter S, Pratt B, Letterio JJ, Paul WE, Berzofsky JA (2003) Transforming Growth Factor-b production and myeloid cells are an effector mechanism through which CD1d-restricted T cells block Cytotoxic T Lymphocyte-mediated tumor immunosurveillance: abrogation prevents tumor recurrence. J Exp Med 198:1741
Terabe M, Park JM, Berzofsky JA (2003) Role of IL-13 in negative regulation of anti-tumor immunity. Cancer Immunol Immunother 53:79
Terabe M, Swann J, Ambrosino E, Sinha P, Takaku S, Hayakawa Y, Godfrey DI, Ostrand-Rosenberg S, Smyth MJ, Berzofsky JA (2005) A nonclassical non-Va14Ja18 CD1d-restricted (type II) NKT cell is sufficient for down-regulation of tumor immunosurveillance. J Exp Med 202:1627
Toura I, Kawano T, Akutsu Y, Nakayama T, Ochiai T, Taniguchi M (1999) Cutting edge: inhibition of experimental tumor metastasis by dendritic cells pulsed with alpha-galactosylceramide. J Immunol 163:2387
Tupin E, Kinjo Y, Kronenberg M (2007) The unique role of natural killer T cells in the response to microorganisms. Nat Rev Microbiol 5:405
Van Rhijn I, Young DC, Im JS, Levery SB, Illarionov PA, Besra GS, Porcelli SA, Gumperz J, Cheng TY, Moody DB (2004) CD1d-restricted T cell activation by nonlipidic small molecules. Proc Natl Acad Sci USA 101:13578
Wilson SB, Delovitch TL (2003) Janus-like role of regulatory iNKT cells in autoimmune disease and tumour immunity. Nat Rev Immunol 3:211
Zhou D, Mattner J, Cantu C 3rd, Schrantz N, Yin N, Gao Y, Sagiv Y, Hudspeth K, Wu YP, Yamashita T, Teneberg S, Wang D, Proia RL, Levery SB, Savage PB, Teyton L, Bendelac A (2004) Lysosomal glycosphingolipid recognition by NKT cells. Science 306:1786
Acknowledgments
We thank our collaborators Elena Ambrosino, Mark Smyth, Jeremy Swann, Yoshihiro Hayakawa, Dale Godfrey, Suzanne Ostrand-Rosenberg, Pratima Sinha, Shun Takaku, Judy Peng, Takashi Yamamura, Sachiko Miyake, Vipin Kumar, and Ramesh Halder for their most valuable collaboration, without which the work reviewed here would not have been possible.
Author information
Authors and Affiliations
Corresponding authors
Additional information
This article is a symposium paper from the conference “Progress in Vaccination against Cancer 2007 (PIVAC 7)”, held in Stockholm, Sweden, on 10–11 September 2007.
Rights and permissions
About this article
Cite this article
Berzofsky, J.A., Terabe, M. A novel immunoregulatory axis of NKT cell subsets regulating tumor immunity. Cancer Immunol Immunother 57, 1679–1683 (2008). https://doi.org/10.1007/s00262-008-0495-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00262-008-0495-4