The yin-yang in immunity

Comment on Borg et al, page 3267, and Zhang et al, page 3276

In this issue of Blood, the natural killer (NK) cell is described in terms of its dendritic cell immune synapse and its effector functions as regulated by the transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ). Such studies of NK cell biology are essential for understanding basic issues in immunology and for effective application of cell-based immunotherapies.

Dendritic cells (DCs) and natural killer (NK) cells are providing essential functions in immunity by initiating immune responses and integrating an orderly transition from innate to adaptive immunity. It is now becoming increasingly evident that these 2 cell types through their mutual interactions coordinate and mediate many of these effects.

There are 2 papers in this issue of the journal that address important aspects of NK cell and NK-DC immunobiology. Zhang and colleagues report that the transcription factor peroxisome proliferator-activated receptor-γ (PPAR-γ) in NK cells reduces interferon γ (IFN-γ) production without any effect on NK cytotoxicity. In contrast, some ligands for PPAR-γ inhibit both IFN-γ production and cytotoxicity, while others have differential effects. Since some long-chain unsaturated fatty acids are potential natural ligands for PPAR-γ, these studies support the concept that PPAR-γ and its ligands are potential targets for regulation of NK cell function and differentiation. The second paper, by Borg and colleagues, describes the NK-DC immune synapse and the requirements for the formation of a productive NK-DC synapse. The authors demonstrate how activation of NK cells by interleukin-12 (IL-12) requires mature DCs (mDCs) and that the activation depends upon both cell-cell contact and remodeling of actin cytoskeleton in the DC.

NK cells can be divided into 2 populations: CD56^bright and CD56^dim. CD56^bright NK cells constitute a minor population in the periphery, while they are the dominating NK cell population in lymphoid tissues. They express high-affinity IL-2 receptor, the lymph node homing receptors CXC chemokine receptor 3 (CXCR3) and CC chemokine receptor 7 (CCR7), and L-selectin. They also express the inhibitory receptor CD94:NKG2A with ligand specificity for HLA-E, but lack the killer inhibitory Ig-like receptors (KIRs), which have ligand specificity for classical HLA class I molecules. Functionally, these NK cells are potent cytokine producers but have minimal cytotoxic capacity. CD56^dim NK cells have a different phenotype; they lack L-selectin, express the chemokine receptors CXCR1 and CX3CR1, readily migrate to inflammatory tissues in response to IL-8, and have high cytotoxic potentials.

During an immune response to a pathogen, immature DCs (iDCs) located in peripheral tissues take up pathogens and become mDCs that are transported to secondary lymphoid tissues, where the immune response is initiated. NK cells therefore have the option of interacting with DCs both in the periphery and in lymphoid tissues. In the periphery, iDCs can activate NK cells by their production of the cytokines IL-2, IL-12, IL-15, and IL-18, and DC production of tumor necrosis factor α (TNF-α) will induce NK cytotoxicity. CD56^dim cytotoxic NK cells may in inflammatory tissues remove iDCs due to their low expression of major histocompatibility complex (MHC) class I, while mDCs that have up-regulated MHC class I and express both HLA-E and classical MHC class I molecules are spared. Lysis of iDCs in the periphery may then facilitate local antigen release, antigen uptake, and possibly cross-presentation of antigen. In the lymphoid tissues, mDCs come in contact with CD56^bright NK cells, which become activated by IL-2 and IL-12 produced by the mDCs. This results in NK cell production of IFN-γ and granulocyte-macrophage colony-stimulating factor (GM-CSF), which induce T-helper (Th) cell differentiation and Th1 polarization and promote DC survival and differentiation. Additional cytokines released from the DC will induce NK cell differentiation/maturation and facilitate NK cell exit as mature effector cells.

Borg et al and Zhang et al have both used in vitro studies to address fundamental issues in NK cell biology. Studies of NK-DC interactions in vivo and identification of the location of such events are very limited. Such studies are however essential not only for the understanding of fundamental issues in immunology but also for effective application of dendritic cell– and NK cell–based therapies (eg, tumor vaccines). The recent development of multiphoton intravital microscopy techniques, which provide imaging of cell migration and cell-cell interactions in the extravascular space in 3 dimensions, are likely in the near future to provide important answers to many of these questions.