Editorial: NKT cells: to suppress or not to suppress, that is the question

In this issue of the Journal of Leukocyte Biology, Hegde et al. [1] add evidence to the debate over whether NKT cells have effector or suppressor function. There are two classes of NKT cells, type I or invariant NKT cells and type II or noninvariant NKT cells. In this discussion, NKT cells refer to invariant NKT cells. Although the function of NKT cells following activation with αGalCer or cytokines is well characterized, their role in immunosurveillance remains controversial. NKT cells were shown to have effector function against viral infections and regulatory function in some experimental autoimmune models [2]. To complicate matters further, in tumor immunology, effector and regulatory roles have been assigned to NKT cells, depending on the mouse model [3,4,5]. To elucidate these contradictions, a better understanding of the important interactions that NKT cells have with APCs, such as macrophages and monocytes, under normal physiological conditions, is needed. The authors provide evidence about this issue by examining how human NKT cells affect the function of monocytes. Their findings demonstrated that human NKT cells instructed peripheral blood monocytes to differentiate into cells with a phenotype similar to myeloid DCs and termed these cells NKT-instructed APCs. Treating the NKT-instructed APCs with LPS induced the production of IL-10 instead of IL-12, which was detected with control DCs. Furthermore, the NKT-instructed APCs were not able to induce T cells to produce IFN-γ in a MLR or to induce T cell proliferation.

The central question that still needs to be clarified is how does the function of human NKT cells compare with the reported functions of murine NKT cells. A large number of studies examined the immunotherapeutic potential of NKT cells, as it was discovered that NKT cell TCR agonist αGalCer had strong anti-tumor activity in mice [6]. Subsequent studies examining the anti-tumor activity of αGalCer found that αGalCer induced the expression of effector cytokines such as IFN-γ and TNF-α as a result of strong interactions with APCs. Delivering αGalCer-loaded DCs to tumor-bearing mice also had therapeutic effects that were dependent on NKT cells. These studies demonstrate the important interactions that NKT cells have with APCs in mice. Human NKT cells were also shown to be activated by DCs loaded with αGalCer in vitro. However, clinical trials with αGalCer-loaded DCs or αGalCer delivered as a soluble agent have been unsuccessful [7, 8]. It is not clear if one difference in anti-tumor activity is a result of low NKT cell levels in humans as compared with mice or if there is a functional distinction of the NKT-APC interactions between humans and mice. Whereas a majority of studies focused on mouse NKT cells, the same attention has not been given to the study of human NKT cells because of the difficulty of working with human tissues, but more importantly, because of the relatively low numbers of NKT cells in the peripheral blood of humans (Table 1). To overcome this limitation, Hedge et al. [1] used NKT cell clones for their study. A potential problem with using NKT cell clones is that human NKT cells are a heterogeneous population with functional differences [9]. The authors addressed this issue by studying phenotypically distinct clones and a polyclonal line. However, future studies will have to verify if freshly isolated NKT cells are also able to instruct monocytes to develop into suppressive myeloid APCs.

TABLE 1.

Comparison of Human and Mouse NKT Cells

	Human	Mouse
Subsets
CD4+CD8−	Present	Present
CD4−CD8+	Present	Absent
CD4−CD8−	Present	Present
Class
Invariant NKT (Type I)	Minor population of NKT cells	Major population of NKT cells
Non-invant NKT (Type II)	Major population of NKT cells	Minor population of NKT cells
Cytokine expression
Th2 (IL-4, IL-5, IL-3, IL-10)	CD4+	CD4+ and DN
Th1 (IFNγ, TNFα)	CD4+, CD8+, and DN	CD4+ and DN
Frequency
Blood	0.001–0.5%	0.2–1%
Liver	∼1%	20–40%

DN, Double-negative (CD4⁻CD8⁻) 

Clearly based on murine studies, NKT cells can have suppressor or effector immune function that depends on the mode of activation. The present study suggests that normal interaction of NKT cells with monocytes induces them to be tolerogenic. Although numerous studies have shown that activated NKT cells can induce APCs to become proinflammatory, Hedge et al. [1] found that even when monocytes were exposed in trans-well to NKT cells pulsed with αGalCer-loaded monocytes, they still were unable to induce IFN-γ and T cell proliferation compared with control DCs. This suggests a unique relationship exists between NKT cells and monocytes that initiates local tolerance. Evidence for this relationship might exist at the human maternal-fetal interface, where tolerance of the mother-to-fetal allograft is needed. At this interface, human NKT cells are found at 10 times the frequency normally found in the peripheral blood [10] and where trophoblasts secrete CXCL16, a chemokine that recruits monocytes [11]. Future work examining NKT-APC interactions is needed, and understanding these events may lead to therapeutic strategies against autoimmune diseases.