In this field, several recent observations have been published. Some authors only investigate CD56bright CD16− NK cells, whereas others also include CD56bright CD16dim NK cells in their studies. We suggest that this point should be harmonized between different groups interested in the topic, and to follow the leader in the field, Michael A. Caligiuri1, who always considers both subpopulations together as CD56bright NK cells. Indeed, there is no obvious reason to ignore the CD56bright CD16dim subset.
Expansion of CD56bright NK cells
In healthy donors, not more than 10% of all peripheral blood NK cells are usually CD56bright. However, expansions above this low percentage have been described during reconstitution of the immune system after bone marrow transplantation, where the first lymphocytes to appear in blood are CD56bright NK cells.31 This population also increases in patients who are treated daily with a low dose of IL-2.31
Interestingly, there are increasing numbers of papers describing expansions of CD56bright NK cells in different diseases, and the list is probably far from being finished.
Our group32 has shown that in two cases of transporter associated with antigen processing (TAP) deficiency, which is characterized biologically by a very low amount of surface expression of HLA class I molecules, and clinically by chronic respiratory infections, bronchiectasis and deep skin ulcers, CD56bright NK cells represent 37% and 54%, respectively, of all peripheral blood NK cells. This was recently confirmed, although to a lesser extent, in a new case of TAP deficiency.33 Interestingly, asymptomatic TAP-deficient patients have normal percentages of CD56bright NK cells.32 In the first study, we compared the TAP-deficient patients with a small series of individuals with vasculitis or with respiratory diseases of other origins. The percentage of CD56bright NK cells was higher than 10% (12·60–25·52%) in approximately one-third of them.32 These data suggest that the expansion of CD56bright NK cells is in no way a hallmark of TAP deficiency, but can occur in several diseases of other origins.
In favour of this interpretation, Cac and Ballas34 present the observation of a woman with recalcitrant and treatment-resistant periungual warts. Flow cytometry revealed that 13·30% of her lymphocytes (and not of her NK cells, which makes the expansion quite dramatic) were CD56bright and only 0·83% of the lymphocytes were CD56dim. Not surprisingly, the patient had a severe reduction in NK cell-mediated cytotoxicity. The warts almost disappeared and NK cell cytotoxicity was restored upon treatment with IFN-α, whereas the proportion of CD56bright NK cells decreased. It is well known that IFN-α stimulates the cytotoxicity of NK cells, but maybe it also favours the maturation of NK cells towards the CD56dim stage. This process was probably blocked before the introduction of IFN-α, but for completely unknown reasons.
An inverse situation is described by Saraste et al.35who treated a group of 11 multiple sclerosis patients with IFN-β and observed an expansion of CD56bright NK cells with a concomitant decrease of CD56dim cells after 12 months of treatment (14·7 ± 2·5% of all NK cells were CD56bright).
In another series of 22 multiple sclerosis patients36 a combined treatment with IFN-β and daclizumab was administered. Daclizumab is a humanized monoclonal antibody directed against the IL-2 receptor α chain (CD25) that was very efficient in stabilizing multiple sclerosis in clinical trials. Also in this case, an expansion of CD56bright NK cells, which correlated with a reduction in brain inflammation, was observed during treatment. The mechanism of action most likely corresponds to an upregulation of CD122 (β chain of the IL-2 receptor) with a better response to endogenous IL-2 as a consequence. In vitro, NK cells from the patients inhibited T-cell proliferation in a contact-dependent manner and are therefore considered as regulatory NK cells by the authors.
A study using daclizumab in five patients with active uveitis37confirmed its therapeutic efficiency on the one hand and the selective expansion of CD56bright NK cells over time (it ranged from fourfold to 20-fold) on the other hand. The CD56bright NK cells produced high amounts of the immunosuppressive cytokine IL-10, and this molecule might be at the origin of the beneficial effect by downregulating the autoimmune response. It is tempting to speculate that CD56bright-mediated secretion of IL-10 explains the therapeutic effects in the three studies presented. Likewise, an efficient immune response against human papillomavirus-induced periungual warts in the case described by Cac and Ballas34 might have been precluded because of the IL-10 production by the abundant CD56bright NK cells. In this context, the concept of regulatory NK cells (‘NKreg’) is clearly emerging in the literature22,38 and deserves further investigation to check, for example, if the entire CD56bright population or only a subset have immunoregulatory properties.
In a case report of a human herpes virus type 6-associated acute necrotizing encephalopathy in a young child, Kubo et al.39 likewise noticed a dramatic expansion of CD56bright NK cells during the convalescent phase. Here, the authors speculate, without any demonstration, that the CD56bright NK cells produce high levels of inflammatory cytokines (indeed found in the serum of the patient) and that a high percentage of these cells is a risk factor for the development of encephalitis during infection with human herpes virus type 6.
A patient with X-linked severe combined immunodeficiency with Omenn syndrome-like manifestations40 had increased circulating NK cells (59·50% of lymphocytes), half of them (28·50%) being CD56bright CD16−. The skin, displaying marked thickening and severe erythema, was infiltrated predominantly by CD56bright CD16− NK cells expressing high levels of messenger RNA for not only inflammatory cytokines but also for IL-10.
In a cohort of female patients chronically infected with hepatitis C virus (HCV)41 compared with HCV resolvers and normal uninfected controls, total NK cell percentages among lymphocytes were reduced in the first group whereas the proportion of CD56bright cells among total NK cells was increased. These cells produced more IFN-γ than CD56bright NK cells from the other two groups, and overall NK cell cytotoxicity was not impaired.
Exactly the same picture, i.e. reduction of NK cell numbers but increased percentage of CD56bright NK cells, was found among individuals with a positive tuberculin skin test (TST+) compared with patients with overt tuberculosis and normal controls.42
The significance of the observations from these two studies is currently unclear. In the case of HCV infection, the authors41 speculate that CD56bright NK cells might contribute to T-cell polarization and liver damage, and that their expansion might be the result of a decreased rate of differentiation towards CD56dim cells. The TST+ subjects might be protected from active tuberculosis by the CD56bright NK cells secreting high amounts of IFN-γ.42
Schepis et al.43 describe an increased proportion of CD56bright NK cells in systemic lupus erythematosus regardless of disease activity. However, the authors do not consider nor do they investigate CD56bright CD16dim cells, their gating strategy does not exclude CD56dim CD16− cells, and finally, as most patients have one or more treatments at the time of blood drawing, the potential role of these treatments in the CD56bright NK cell expansion is not considered. Nevertheless, systemic lupus erythematosus might be added to the growing list of diseases characterized by an increased proportion of CD56bright NK cells, although this topic deserves further investigation.
Although they unfortunately do not discriminate between CD56bright and CD56dim NK cells, three papers44–46 describe a dramatic expansion of NKG2C+ NK cells in human infections caused by human immunodeficiency virus type 1 and cytomegalovirus. As a subset of CD56bright NK cells expresses NKG2C,47 this discrimination would be very interesting and important to make in future investigations.
Whereas the studies presented so far all deal with peripheral blood NK cells, others describe the presence of CD56bright NK cells in different tissues during disease states. CD56bright CD16− KIR– NK cells are found, among other cell types, within acute psoriatric plaques and abundantly produce IFN-γ upon stimulation.48 In rheumatoid arthritis, the proportions of different peripheral blood NK cell subsets are the same as in healthy donors, but the synovial fluid of the patients almost exclusively contains CD56bright KIR– NK cells.49 Likewise in sarcoidosis,50 no difference is observed between patients and normal controls in peripheral blood, whereas the former have more CD56bright NK cells in their bronchoalveolar lavage fluid.
Reduction of CD56bright NK cells
Interestingly, several recent observations show that in some diseases, the percentage of CD56bright NK cells is reduced. In patients with coronary heart disease,51 overall NK cell numbers are diminished as is the cytotoxic activity, and in addition, there is a tendency towards lower percentages of CD56bright NK cells in the patients compared with normal controls. The rationale of this study was the fact that infections are considered to be a risk factor for coronary heart disease and that NK cells participate in immune responses against viruses and bacteria.
By analysing a small series of patients with allergic rhinitis and/or asthma, Scordamaglia et al.52 found a significantly reduced percentage of CD56bright NK cells compared with non-allergic individuals. The consequences are a weak IFN-γ production and impaired interactions with DC, so that in allergic diseases, NK cells might be unable to sufficiently shape adaptive immunity in the T helper type 1 direction. All these data will have to be confirmed by larger series but they provide interesting indications.
In juvenile rheumatoid arthritis with systemic onset, not only is the NK cell cytotoxic activity strongly reduced, but in some patients, the total absence of CD56bright NK cells has been described.53 The same phenomenon had previously been found in patients with macrophage activation syndrome and haemophagocytic lymphohistiocytosis. The authors suggest, without demonstrating it, that the CD56bright NK cells have all been recruited to the sites of inflammation. It would be very interesting to check if in these patients, CD56bright NK cells are found in the LN or in the synovium for example. If not, one would have to ask the question how CD56dim NK cells can arise in the absence of CD56bright precursors.