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NKT Cells Are Stunned by Α- Galactosylceramide

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NKT Cells Are Stunned by Α- Galactosylceramide Activation or anergy: NKT cells are stunned by α- galactosylceramide Barbara A. Sullivan, Mitchell Kronenberg J Clin Invest. 2005;115(9):2328-2329. https://doi.org/10.1172/JCI26297. Commentary Invariant natural killer T (iNKT) cells are T lymphocytes that behave similarly to cells of the innate immune system. The glycolipid α-galactosylceramide (α-GalCer) is a potent and specific activator of mouse and human iNKT cells and has been used in cancer clinical trials to drive NKT cell–mediated immune responses. However, little is known about the dynamics of the iNKT cell response to α-GalCer in vivo. In this issue of theJ CI, Parekh and colleagues demonstrate that administration of α-GalCer causes iNKT cells to become unresponsive, for at least 1 month, in mice. This leads us to ask, should sequential administration of α-GalCer still be used to activate iNKT cells given the anergic state it has been shown here to induce? This intriguing article raises the issue of the avoidance of anergy induction in the design of treatment regimens that use α-GalCer as a specific activator of iNKT cells. Find the latest version: https://jci.me/26297/pdf commentaries Activation or anergy: NKT cells are stunned by α-galactosylceramide Barbara A. Sullivan and Mitchell Kronenberg La Jolla Institute for Allergy and Immunology, San Diego, California, USA. Invariant natural killer T (iNKT) cells are T lymphocytes that behave simi- repeated α-GalCer administration in vivo. larly to cells of the innate immune system. The glycolipid α-galactosylce- In this issue of the JCI, Parekh et al. pro- ramide (α-GalCer) is a potent and specific activator of mouse and human vide what we believe to be the first descrip- iNKT cells and has been used in cancer clinical trials to drive NKT cell–medi- tion of the detailed long-term effects of ated immune responses. However, little is known about the dynamics of the α-GalCer administration on iNKT cells in iNKT cell response to α-GalCer in vivo. In this issue of the JCI, Parekh and vivo, in mice (11). colleagues demonstrate that administration of α-GalCer causes iNKT cells Parekh et al. (11) have demonstrated to become unresponsive, for at least 1 month, in mice (see the related article that a single injection of α-GalCer induces beginning on page 2572). This leads us to ask, should sequential administra- long-term anergy of iNKT cells in mice. tion of α-GalCer still be used to activate iNKT cells given the anergic state it What exactly is anergy? Ronald Schwartz, has been shown here to induce? This intriguing article raises the issue of the a pioneer in this field of study, calls it “a avoidance of anergy induction in the design of treatment regimens that use tolerance mechanism in which the lym- α-GalCer as a specific activator of iNKT cells. phocyte is intrinsically functionally inac- tivated following an antigen encounter, Natural killer T (NKT) cells are specialized a screen for antitumor activity of com- but remains alive for an extended period T cells of the immune system that express pounds derived from marine sponges of time in a hyporesponsive state” (12). markers of the NK cell lineage, such as NK1.1. (2). In mice, α-GalCer activates iNKT Simply put, conventional T cells can be They recognize glycolipid antigens presented cells within hours of injection, causing “stunned” by strong TCR signals delivered by the MHC class I–related protein CD1d (1). these cells to produce copious amounts in the absence of costimulation. The iNKT In mice, these cells are sometimes referred to of both regulatory and proinflammatory cell anergy described by Parekh et al. has as invariant NKT (iNKT) cells, because they cytokines. Proinflammatory cytokines several features in common with the aner- express an invariant TCR consisting of a lead to the downstream transactivation of gy of conventional T cells, as it is long last- single Vα-to-Jα rearrangement (Vα14-Jα18), NK, T, and B cells as well as DCs. The NK ing, independent of persistent antigen, cell paired with a restricted set of Vβ chains cell activation that is dependent on acti- autonomous, and reversible with adminis- (Vβ8.2, Vβ7, and Vβ2 are most common). vated iNKT cells is essential for α-GalCer– tration of IL-2 (11). The authors also show Human iNKT cell TCRs express orthologous mediated tumor clearance in mice. Coad- that, as for conventional T cells, the block V segments, an invariant Vα24-Jα18 paired ministration of a model protein antigen in activation of anergized iNKT cells is at with Vβ11. Human and mouse iNKT cells with α-GalCer leads to the enhanced the level of the TCR. Culture of anergized react to the same glycolipid antigens, includ- induction of specific T cell memory (3, 4). iNKT cells with PMA plus ionomycin, ing α-galactosylceramide (α-GalCer), which α-GalCer is highly potent because of its which bypasses proximal steps in TCR sig- is presented by CD1d. Among T lympho- strong binding to the iNKT cell TCR naling, allowed the iNKT cells to respond cytes, iNKT cells are unique in terms of the and its long half-life (5). Additionally, by producing cytokines. conservation of their specificity and activated α-GalCer targets only iNKT cells, as there Do iNKT cells become anergic when acti- phenotype; this suggests that studies eluci- is little bystander activation and little vated without costimulation? Parekh et al. dating key components of mouse iNKT cell transactivation in mice lacking CD1d. do not address this issue directly; however, biology will likely also prove important for Numerous investigators have used syn- they do show that B cells presenting α-Gal- human iNKT cells. However, humans have thetic α-GalCer, or its variants, in mouse Cer can induce anergy in iNKT cells whereas fewer CD1d-restricted iNKT cells than mice. models to prevent tumor metastases, to DCs do not (11). They speculate that this is reduce autoimmunity in experimental due to the numbers of costimulatory mol- α-GalCer activates and autoimmune encephalomyelitis (EAE) ecules present on the surface of each cell anergizes iNKT cells and diabetes models, and to enhance the type, with B cells having low numbers and The glycolipid α-GalCer (also called responses to viral and parasitic infections DCs having higher numbers. Unlike con- KRN7000) was originally identified in (6). Furthermore, α-GalCer has been used ventional T cells, iNKT cells do not require in 4 phase I cancer clinical trials to date, costimulation for rapid cytokine release Nonstandard abbreviations used: α-GalCer, α-galac- with the ultimate purpose of determining (13). Mouse iNKT cells may be activated tosylceramide; iNKT, invariant natural killer T (cell); whether the antitumor effects obtained initially in response to antigen and expand NKT, natural killer T (cell). in mice also will be observed in humans in number without costimulation, but may Conflict of interest: The authors have declared that no conflict of interest exists. (7–10). Despite the interest in using then adopt an anergic state. iNKT cell aner- Citation for this article: J. Clin. Invest. 115:2328–2329 α-GalCer in the clinic to activate iNKT gy therefore may not be mechanistically (2005). doi:10.1172/JCI26297. cells, little is known about the effects of identical to conventional T cell anergy. 2328 The Journal of Clinical Investigation http://www.jci.org Volume 115 Number 9 September 2005 commentaries In some cases, anergic cells also regulate 3 immunizations with α-GalCer–loaded CD8 T cell immunity to a coadministered protein. J. Exp. Med. 198:267–279. the activation of other T cells. This does mature DCs (10). 4. Gonzalez-Aseguinolaza, G., et al. 2002. Natural kill- not seem to be the case for iNKT cells, and What are the prospects for using gly- er T cell ligand alpha-galactosylceramide enhances they do not express Foxp3 (11), the tran- colipid agonists to activate iNKT cells in protective immunity induced by malaria vaccines. scription factor that acts as a master regu- vivo? iNKT cells are an exceptional tar- J. Exp. Med. 195:617–624. 5. Sidobre, S., et al. 2004. The T cell antigen receptor lator for the generation and function of get for immunotherapy, because of their expressed by Valpha14i NKT cells has a unique CD25+ Tregs. iNKT cells normally produce swift and directed activation of the adap- mode of glycosphingolipid antigen recognition. both IFN-γ and IL-4 when activated by tive immune system. However, it might Proc. Natl. Acad. Sci. U. S. A. 101:12254–12259. 6. Godfrey, D.I., and Kronenberg, M. 2004. Going α-GalCer, but Parekh et al. also show that be worthwhile to investigate iNKT cell both ways: immune regulation via CD1d-dependent while iNKT cell anergy is characterized anergy further in the context of targeting NKT cells [review]. J. Clin. Invest. 114:1379–1388. by a reduction in IL-4 production, there α-GalCer to different APCs. Furthermore, doi:10.1172/JCI200423594. 7. Giaccone, G., et al. 2002. A phase I study of the nat- is a more severe drop in IFN-γ produc- new glycolipid ligands for iNKT cells ural killer T-cell ligand alpha-galactosylceramide tion (11). iNKT cell anergy may therefore have been recently identified, including (KRN7000) in patients with solid tumors. Clin. potentially skew Th2 cytokine production, synthetic and naturally occurring anti- Cancer Res. 8:3702–3709. 8. Nieda, M., et al. 2004. Therapeutic activation of a fact that might explain the beneficial gens. The naturally occurring antigens Valpha24+Vbeta11+ NKT cells in human subjects effects of repeated α-GalCer treatment in isoglobotrihexosylceramide (iGb3; an results in highly coordinated secondary activation of the prevention of spontaneous diabetes in autologous mouse antigen [ref.
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