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Originally published online as doi:10.1189/jlb.0104038 on May 24, 2004 Originally published online as doi:10.1189/jlb.0104038 on May 3, 2004

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(Journal of Leukocyte Biology. 2004;76:307-313.)
© 2004 by Society for Leukocyte Biology

CD1d-restricted "NKT" cells and myeloid IL-12 production: an immunological crossroads leading to promotion or suppression of effective anti-tumor immune responses?

Jenny E. Gumperz1

Department of Medical Microbiology and Immunology, University of Wisconsin Medical School, Madison

1Correspondence: Department of Medical Microbiology and Immunology, University of Wisconsin Medical School, Service Memorial Institutes, Room 405, 1300 University Ave., Madison, WI 53706. E-mail: jegumperz{at}wisc.edu


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ABSTRACT
 
CD1d-restricted T cells are remarkable for their unusual ability to respond to self-antigens and to contribute to both immunostimulatory and immunosuppressive responses. Their effects in different cancer models have appeared contradictory; in some cases, they are linked to the generation of effective tumor clearance, and in others, they seem to contribute to suppression of anti-tumor responses. Recent results suggest CD1d-restricted T cells are involved in critical interactions with myeloid dendritic cells (DCs) that can affect the subsequent course of the immune response, and that factors such as the strength of the antigenic signal and the presence or absence of proinflammatory cytokines may determine the outcome of these interactions. In the presence of a strong antigenic signal, CD1d-restricted T cells induced myeloid DCs to secrete interleukin (IL)-12, and these DCs in turn activated naive T cells to secrete Th1 cytokines. When exposed to the weak antigenic stimulus of self-antigens, CD1d-restricted T cells induced DCs to secrete IL-10 but not IL-12, and these DCs failed to stimulate Th1 cytokine production by naive T cells. In contrast, CD1d-restricted T cells that were stimulated by self-antigens in the presence of IL-12 potently secreted interferon-{gamma} (IFN-{gamma}) and were among the first lymphocytes to become activated in vivo. Hence, CD1d-restricted T cells may promote or prevent effective anti-tumor responses that are mediated by other lymphocytic effector cells by influencing IL-12 production by myeloid DCs and by their own production of early IFN-{gamma} in response to IL-12.

Key Words: {alpha}-galactosylceramide • IFN-{gamma} • dendritic cells


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WHAT ARE NATURAL KILLER T (NKT) CELLS?
 
NKT cells are a small subset of T cells that has attracted a great deal of attention in recent years. The interest in NKT cells stems from their increasingly well-recognized ability to contribute in a remarkable variety of immunological contexts, including microbial infections, cancer, autoimmunity, and allergy (see refs. [1 2 3 4 ] for review). Nevertheless, this T cell subset remains a puzzle to many, starting with the basic question, "What is an NKT cell?" (See refs. [5 , 6 ] for excellent discussions of this question.)

NKT cells were originally defined as a subset of T cells that coexpresses CD161 (previously known as NKR-P1 or NK1.1), a molecule that is constitutively expressed on NK cells and is encoded in the NK complex [7 8 9 10 ]. These T cells were found to potently produce cytokines upon CD3 cross-linking and without requiring prior exposure to foreign antigens [7 , 11 , 12 ], which led to the speculation that they may comprise a T cell subset that has innate functions [13 ]. However, it is now clear that although CD161+ T cells are a functionally distinctive and relatively homogeneous subset in naive mice, CD161 can become up-regulated on a wide variety of T cells in vivo upon activation or under conditions of inflammation [14 15 16 17 ]. Thus, T cell expression of CD161 is not a stable marker that defines a functional subset, but rather is likely to reflect a heightened state of activation (see ref. [18 ] for discussion). Consistent with this notion, human T cells that express CD161 appear strongly biased toward cells with a memory/activated phenotype, are heterogeneous with regard to T cell receptor (TCR) and coreceptor expression, and on average, comprise ~25% of the total T cells rather than the small percentage observed in naive mice [19 ].

A key breakthrough was the discovery that most of the CD161+ T cells in naive mice are restricted by the nonclassical antigen-presenting molecule, CD1d [20 ]. Not all CD1d-restricted T cells are CD161+, and conversely not all of the T cells in naive mice that co-express CD161 appear to be CD1d restricted. However, importantly, the functional properties that were previously ascribed to NK1.1+ T cells now appear to be largely due to CD1d-restricted T cells [21 , 22 ]. CD1d-restricted T cells detected in human peripheral blood samples are present at low frequencies (usually 0.05–0.5% of the total T cells) and make up only a small fraction of the CD161+ T cells, but like their murine counterparts, also demonstrate potent production of both T helper cell type 1 (Th1) and Th2 cytokines and have an activated/memory phenotype [23 , 24 ].


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CD1 MOLECULES AND CD1d-RESTRICTED T CELLS
 
CD1 molecules are ß2 microglobulin-associated cell-surface glycoproteins that resemble class I molecules in overall domain structure, and are mainly expressed on antigen-presenting cells (APCs), including monocytes, macrophages, dendritic cells (DCs), and B cells [25 ]. Five distinct CD1 isoforms are expressed in humans (CD1a, -b, -c, -d, and -e); however, mice and rats possess only CD1d, and consequently, this is the best-studied member of the CD1 family. Unlike classical antigen-presenting molecules, which present peptide antigens, CD1 molecules have been shown to present lipid and glycolipid antigens to T cells [26 27 28 ]. Recent crystal structures of CD1 molecules with bound lipid ligands indicate that the alkyl chains of the lipid are sequestered within the hydrophobic binding cleft of the CD1 molecule, and portions of the more polar head group remain surface-accessible [29 , 30 ]. As the alkyl chains are relatively structurally homogeneous, and the head groups of lipids and glycolipids can be extremely structurally diverse, this system provides a means by which a wide variety of lipids can be presented by CD1 molecules, and subtle differences in the head groups can be distinguished as antigenic features by CD1-restricted T cells [31 ].

Despite the progress in understanding CD1-mediated antigen presentation, little is known about the identity of the physiological antigens recognized by CD1d-restricted T cells. An unusual glycolipid, {alpha}-galactosylceramide ({alpha}-GalCer), which was originally purified from a species of marine sponge, has been found to potently activate a large fraction of CD1d-restricted T cells [32 ]. This glycolipid is related to ceramide-type sphingolipids that are common in mammalian cells, but it contains key structural differences that apparently confer its strong antigenicity, and it is currently unclear whether analogs of this molecule exist that function as physiological antigens.

Many CD1d-restricted T cells also show modest responses to CD1d molecules expressed at the surface of APCs in the absence of exogenously added antigens [20 , 33 34 35 ]. Using murine CD1d-restricted T cell hybridomas and recombinant CD1d molecules that can be loaded with lipid antigens in aqueous solution, co-workers and I [36 ] demonstrated directly that these responses are likely a result of recognition of specific cellular antigens presented by CD1d. The murine T cell hybridomas responded well to CD1d-transfected APCs in the absence of exogenously added antigens, but showed little or no response to plate-bound recombinant CD1d molecules. However, they responded robustly to the recombinant CD1d after pretreatment with {alpha}-GalCer, indicating that these CD1d molecules could be recognized if they contained an appropriate lipid ligand. Importantly, a CD1d-dependent response was also observed when the recombinant CD1d molecules were pretreated with a fraction of a cellular extract that contained the lipids, and one hybridoma responded specifically to subfractions that contained the cellular phospholipids, as well as to certain purified and synthetic phospholipids [36 , 37 ]. These results suggested that reactivity to cell-surface CD1d molecules is due to recognition of specific cellular antigens that are not present in the recombinant CD1d molecules. Similarly, it is clear that many human CD1d-restricted T cells respond strongly to {alpha}-GalCer presented by CD1d (Fig. 1a and b ) but also can show modest responses to cell-surface CD1d in the absence of added antigens (Fig. 1b ; see ref. [38 ]), and these responses can be blocked by the addition of an anti-CD1d antibody (Fig. 1c ; see ref. [38 ]). Thus, both murine and human CD1d-restricted T cells appear to demonstrate higher levels of overt reactivity to self-antigens than classical, peptide-specific T cells. However, as this autoreactive recognition generally elicits only relatively weak T cell responses, it has remained unclear whether it is physiologically relevant. Our results suggesting that these low-level responses may translate into important physiological effects with different functional outcomes that vary according to the context, will be discussed below.



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  		Figure 1. Many CD1d-restricted T cells show strong responses to the unusual glycolipid {alpha}-GalCer but also show weak responses to CD1d molecules on APCs in the absence of added antigens. (a) A human CD1d-restricted T cell clone was tested for cytokine secretion in response to recombinant plate-bound CD1d-Fc fusion protein or an isotype-matched, negative-control monoclonal antibody (mAb). No significant interferon-{gamma} (IFN-{gamma}) was detected in response to the negative-control mAb or to the CD1d-Fc fusion protein that was pretreated with vehicle alone (middle bar), whereas CD1d-Fc fusion protein that was pretreated with {alpha}-GalCer (right-hand bar), elicited marked IFN-{gamma} secretion. No significant cytokine secretion was observed in response to negative-control mAb that was pretreated with {alpha}-GalCer (data not shown; see ref. [36 ]). (b) A CD1d-restricted human T cell clone was tested for cytokine secretion in response to untransfected or CD1d-transfected HeLa cells. Solid bars show interleukin (IL)-4 detected in the culture supernatant of a CD1d-restricted clone, which was exposed to HeLa cells in the presence of {alpha}-GalCer, and open bars show the response to HeLa cells in the presence of vehicle alone. Ag, Antigen. (c) A CD1d-restricted human T cell clone was tested for proliferation in response to human in vitro-derived immature DCs in the presence of vehicle alone (T cells+DCs) or with {alpha}-GalCer (T cells+DCs+{alpha}-GalCer). Solid bars show the proliferative response with an isotype-matched, negative-control mAb, and hatched bars show the response in the presence of an anti-CD1d-blocking mAb. In all plots, error bars show the standard deviation of the mean.


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CD1d-RESTRICTED T CELLS IN CANCER MODELS
 
CD1d-restricted T cells are associated with potent rejection of implanted tumors or with the ability to effectively control the outgrowth of endogenously arising tumors in a number of model systems. Pharmacological activation of CD1d-restricted T cells by systemic administration of {alpha}-GalCer results in successful tumor rejection, and injection of {alpha}-GalCer pre-pulsed DCs appears to promote an even stronger anti-tumor response [32 , 39 , 40 ]. The mechanisms involved in the {alpha}-GalCer-induced anti-tumor effects are not yet completely clear. However, administration of {alpha}-GalCer has been shown to induce rapid and potent production of IFN-{gamma} and to lead to widespread immune activation, including activation of NK cells, other T cells, and B cells—effects that likely contribute to the observed, anti-tumor responses [41 , 42 ]. Moreover, CD1d-restricted T cell recognition of {alpha}-GalCer leads to up-regulation of CD40L, which binds to CD40 on myeloid DCs, leading to enhanced IL-12 secretion [43 ]. Hence, {alpha}-GalCer treatment could also have anti-tumor effects by helping to stimulate endogenous IL-12 production. Interestingly CD1d-deficient mice showed less tumor regression in response to exogenously administered IL-12 than wild-type mice, suggesting that CD1d-restricted T cells can also function to promote tumor rejection "downstream" of IL-12 secretion [44 , 45 ]. Additionally, CD1d-restricted T cells appear to be important for successful anti-tumor responses in vaccine approaches that involve immunization with tumor antigens in combination with an adjuvant or that use irradiated melanoma cells engineered to secrete granulocyte macrophage-colony stimulating factor [46 , 47 ].

In a model system that does not rely on exogenously administered immune activators, CD1d-restricted T cells have been shown to contribute to the control of mutagen-induced sarcomas, suggesting that they can also participate in natural tumor immunosurveillance [48 ]. In this system, the effect of CD1d-restricted T cells apparently occurs via the endogenous IL-12 pathway, and although their early production of IFN-{gamma} appears critical, they do not appear to be the mediators of perforin-dependent tumor cell killing [49 ]. An intriguing recent observation may also support a role for CD1d-restricted T cells in natural, immunological control of nascent, human tumors. CD1d was found to be one of the most significantly down-regulated genes on chronic lymphocytic leukemias from human patients, suggesting its expression may be deleterious for the tumor and therefore that its down-regulation has allowed the tumor to escape an aspect of immunological control [50 ].

Collectively, these studies suggest a model in which CD1d-restricted T cells can stimulate and/or respond to IL-12 production by myeloid cells (e.g., monocytes, macrophages, and immature or mature myeloid DCs). This in turn activates effector lymphocytes, such as NK cells and cytolytic T lymphocytes (CTLs), which mediate cytotoxcity against the tumor cells in response to recognition of specific ligands on the tumors (Fig. 2a ). Additionally, CD1d-restricted T cells may be important as early suppliers of the IFN-{gamma} that is critical for the activation of cytotoxic effector lymphocytes. Moreover, recognition of CD1d on certain types of tumor cells by CD1d-restricted T cells may lead to direct anti-tumor effects. Thus, there is substantial published literature demonstrating that CD1d-restricted T cells can contribute to successful anti-tumor immune responses.



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  		Figure 2. Contrasting roles of CD1d-restricted T cells observed in different cancer model systems. (a) In some models, CD1d-restricted T cells have been implicated in promoting anti-tumor responses. One mechanism by which CD1d-restricted T cells can influence tumor rejection, is up-regulation of CD40L in response to presentation of {alpha}-GalCer by myeloid DCs, which stimulates the DCs to produce IL-12 p70, a potent activator of cytolytic lymphocytes [43 ]. CD1d-restricted T cells are also implicated as early producers of the cytokine IFN-{gamma}, which activates cytolytic lymphocytes, including NK cells and CD8+ CTLs [49 ]. It is unclear whether CD1d-restricted T cells can function as direct cytolytic effectors, but some evidence suggests CD1d expression by tumors might be deleterious [50 ]. (b) In other models, CD1d-restricted T cells are associated with inhibition of anti-tumor immune responses. This effect may relate to IL-13 production by CD1d-restricted T cells, which may inhibit DC production of IL-12 and instead, result in production of transforming growth factor-ß (TGF-ß), a cytokine that inhibits CTL responses [51 52 53 54 ].

Hence, it is paradoxical that in a number of published studies the effect of CD1d-restricted T cells appears, in contrast, to contribute to suppression of effective anti-tumor responses. In one such system, tumors are implanted and initially grow, then regress as a result of an anti-tumor immune response, but then eventually recur as a result of suppression of the anti-tumor immune response [51 ]. CD1d-restricted T cells appeared to contribute to the suppression of tumor-specific CTLs that resulted in diminished immunosurveillance and tumor recurrence. This effect may be related to their production of IL-13, a cytokine that is potently secreted by some CD1d-restricted T cells [52 , 53 ]. IL-13 can serve to inhibit cell-mediated immune responses, perhaps because DCs that are exposed to this cytokine produce more TGF-ß, a factor that has potent, suppressive effects on T cells [54 ]. CD1d-restricted T cells were also found to be critical for the immunosuppressive effects of UV irradiation, which can lead to inhibition of delayed-type hypersensitivity responses and potentially contribute to the outgrowth of UV-induced sarcomas [55 ]. Finally, administration of CpG oligodinucleotides induced potent tumor rejection in CD1d-deficient mice but not in wild-type mice, supporting the possibility that CD1d-restricted T cells could be responsible for a suppressive effect on anti-tumor responses [56 ].

Taken together, these studies suggest that in some cases the functions of CD1d-restricted T cells contribute to the prevention of effective anti-tumor responses. It is presently unclear how this immunosuppressive effect occurs, but one possibility is that CD1d-restricted T cells influence DCs, perhaps via production of IL-13, which leads to decreased IL-12 secretion and/or enhanced TGF-ß production, and these DCs subsequently induce deactivation of tumor-specific CTLs (Fig. 2b) . Our recent results suggest that CD1d-restricted T cells can interact directly with myeloid DCs, and that depending on the strength of the antigenic stimulus and the presence or absence of other costimulating factors, the outcome of these interactions can vary dramatically and could potentially lead to contrasting effects on the subsequent immune response.


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CD1d-RESTRICTED T CELL-MEDIATED DC INSTRUCTION
 
My co-workers [57 ] have recently found that autoreactive human CD1d-restricted T cells can interact with immature myeloid DCs to induce DC maturation. The interaction required T cell recognition of CD1d on the immature DCs, which led to T cell activation (i.e., cytokine secretion and expression of stimulatory cell-surface molecules) that in turn, stimulated the DCs. The DCs appeared to mature mainly as a result of exposure to tumor necrosis factor {alpha} (TNF{alpha}) that was produced by the T cells. However, the DCs acquire different functional properties in their mature state, depending on the type of stimulation they received from the T cells during maturation. When immature DCs were exposed to CD1d-restricted T cells in the presence of the strongly activating ligand {alpha}-GalCer, the resulting mature DCs potently produced IL-12; this appeared to be due to stimulation from CD40L, which is up-regulated on the CD1d-restricted T cells in response to {alpha}-GalCer recognition, as described previously by others [43 , 57 ]. The IL-12-producing DCs efficiently stimulated naive T cells to proliferate and to secrete IFN-{gamma}, suggesting they could have an immunostimulatory effect in vivo. In contrast, when immature DCs were exposed to CD1d-restricted T cells in the absence of {alpha}-GalCer, a condition that only induces modest T cell activation, DC maturation was observed, but the resulting mature DCs produced high levels of IL-10 and little or no detectable IL-12. Naive T cells that were exposed to these DCs were stimulated to proliferate but not to produce IFN-{gamma}, suggesting that these mature DCs could have a tolerizing effect.

Thus, the potency of the antigen presented by CD1d (or the strength of the TCR signal received) may impact the level of CD1d-restricted T cell activation. CD1d-restricted T cells activated to different degrees may induce qualitatively different functions from the DCs with which they interact, resulting in profoundly different effects on the outcome of the subsequent adaptive immune response. Therefore, one explanation for the different effects of CD1d-restricted T cells observed in different cancer model systems is that there could be differences in the level of antigenic stimulation; in some cases, the CD1d-restricted T cell stimulation may be strong enough to induce maturation of immunostimulatory DCs, whereas in others, it is not, and the result is DCs with a tolerizing effect.


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MODULATION OF CD1d-RESTRICTED T CELL RESPONSES TO SELF-ANTIGENS
 
Our recent findings detailing a novel mechanism of CD1d-restricted T cell activation in microbial infections may shed light on how these cells could also contribute to anti-tumor responses downstream of initial myeloid cell IL-12 production. In investigating the mechanism of CD1d-restricted T cell activation in microbial infections, we [38 ] found that CD1d-restricted T cells were among the first lymphocytes to produce IFN-{gamma} during infection with Salmonella typhimurium in vivo. Remarkably, there was no evidence that the CD1d-restricted T cells were responding to specific Salmonella antigens. Instead, we found that IL-12, which was produced by immature myeloid DCs in response to microbial products, powerfully costimulated the weak responses of CD1d-restricted T cells to self-antigens, resulting in significant IFN-{gamma} production but no detectable IL-4 production [38 ]. Thus, CD1d-restricted T cells may be able to function in an "innate-like" manner by responding strongly to self-antigens in the presence of costimulatory molecules that indicate "danger," allowing them to respond rapidly to a wide variety of pathogens. It is interesting that a similar effect has been observed for NK cells, the prototypical innate lymphocytes: Exposure to IL-12 or IL-18 permits NK cells bearing activating Ly-49 receptors (which are normally kept in check by inhibitory Ly-49 receptors) to overcome the inhibitory signals and produce high levels of IFN-{gamma} [58 ].

Hence, both NK cells and NKT cells may function immediately downstream of IL-12 by producing a burst of IFN-{gamma} in response to this cytokine. This effect may be particularly important in anti-tumor immune responses, as early exposure to IFN-{gamma} is critical for the activation of cytolytic effector cells, which mediate tumor clearance. Additionally, this function of CD1d-restricted T cells may play an important role in driving the development of lasting Th1 responses, as exposure to IFN-{gamma} along with other stimulating factors can induce immature DCs to become mature DCs that continue to secrete IL-12 and activate naive T cells to proliferate and produce their own IFN-{gamma} [57 ]. Thus, the ability of CD1d-restricted T cells to promote effective tumor immunosurveillance that is observed in some model systems, could be a result of the availability of sufficient endogenous IL-12 to elicit IFN-{gamma} secretion from the CD1d-restricted T cells, which in turn drives maturation of immunostimulatory DCs. In contrast, observations of CD1d-restricted T cells inhibiting anti-tumor responses could be a result of a lack of endogenous IL-12, in which case, CD1d-restricted T cells might predominantly drive maturation of tolerizing DCs that serve to de-activate tumor-specific CTLs.


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CONCLUSIONS
 
The ability of CD1d-restricted T cells to promote effective anti-tumor immune responses holds significant promise for the development of novel immunotherapies that are designed to exploit the functions of these unique T cells. However, their contradictory effects in different model systems clearly demonstrate that to achieve a reliable therapeutic method, it will be necessary to better understand the parameters that affect the functions of CD1d-restricted T cells. Current strategies focus on providing a strong CD1d-restricted TCR stimulus by administering {alpha}-GalCer or {alpha}-GalCer-pulsed DCs, which generally appears to result in an overall Th1-dominated response. Additionally, an analog of {alpha}-GalCer, {alpha}-C-GalCer, which appears to induce longer term production of IFN-{gamma}, has recently been identified and shown to have superior effects in preventing tumor metastases, although the mechanisms responsible for its effects are not clear [59 ]. The ability of these CD1d-restricted T cell ligands to activate powerful immune responses is unequivocal; however, it remains a concern that both Th1 and Th2 cytokines are elicited, and in some cases, administration of these compounds induces tolerogenic effects—an outcome that is useful for the treatment of autoimmune disease but not desirable for the treatment of cancer [1 , 4 ].

Our results suggest that another way of activating CD1d-restricted T cells to promote anti-tumor responses might be the combination of a weak antigenic stimulus and agents that result in endogenous production of IL-12 by myeloid DCs. The antigenic stimulation provided by self-antigens might be sufficient for this effect, or analogs of {alpha}-GalCer that are weaker agonists could be used [60 ]. Efficient induction of endogenous IL-12 production can be achieved by exposure to a nonlethal bacterial infection, and this is already known to have therapeutic benefit for the treatment of cancer, as observed in the current clinical use of bacillus Calmette-Guerin (BCG) to treat bladder cancer [61 62 63 ]. Hence, an intriguing possibility is that the effects observed from treatments such as BCG, which induce endogenous IL-12, may be dependent on CD1d-restricted T cells or could potentially be augmented by concurrently administering a compound that provides a moderate level of TCR stimulation for CD1d-restricted T cells [60 ].


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ACKNOWLEDGEMENTS
 
The author gratefully acknowledges Dr. Manfred Brigl for insightful discussions and help in generating the figures. J. E. G. is supported by National Institutes of Health Grant R01 HL 071590-01.

Received January 23, 2004; revised April 4, 2004; accepted April 9, 2004.


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