During the innate immune response to infection, monocyte-derived cytokines (monokines), stimulate natural killer (NK) cells to produce immunoregulatory cytokines that are important to the host's early defense. Human NK cell subsets can be distinguished by CD56 surface density expression (ie, CD56 bright and CD56 dim ). In this report, it is shown that CD56 bright NK cells produce significantly greater levels of interferon-␥, tumor necrosis factor-␤, granulocyte macrophage-colony-stimulating factor, IL-10, and IL-13 protein in response to monokine stimulation than do CD56 dim NK cells, which produce negligible amounts of these cytokines. Further, qualitative differences in CD56 bright NK-derived cytokines are shown to be dependent on the specific monokines present. For example, the monokine IL-15 appears to be required for type 2 cytokine produc- IntroductionNatural killer (NK) cells are innate immune effectors that produce immunoregulatory cytokines, such as interferon (IFN)-␥ and granulocyte macrophage-colony-stimulating factor GM-CSF, critical to early host defense against a variety of viral, bacterial, and parasitic pathogens. [1][2][3][4] Human NK cells comprise approximately 10% of all peripheral blood lymphocytes and are characterized phenotypically by the presence of CD56 and the lack of CD3. 1 There are 2 distinct subsets of human NK cells identified by cell surface density of CD56. The majority (approximately 90%) of human NK cells are CD56 dim and express high levels of Fc␥RIII (CD16), whereas a minority (approximately 10%) are CD56 bright and CD16 dim/neg . 5 CD56 bright NK cells constitutively express the high-and intermediate-affinity IL-2 receptors and expand in vitro and in vivo in response to low (picomolar) doses of IL-2. [6][7][8] These NK cells also express the c-kit receptor tyrosine kinase whose ligand enhances IL-2-induced proliferation. 9,10 In contrast, resting CD56 dim NK cells express only the intermediate affinity IL-2 receptor, are c-kit neg , and proliferate weakly in response to high doses of IL-2 (1 to 10 nM) in vitro, even after induction of the high-affinity IL-2 receptor. 6,7 Resting CD56 dim NK cells are more cytotoxic against NK-sensitive targets than CD56 bright NK cells. 11 However, after activation with IL-2 or IL-12, CD56 bright cells exhibit similar or enhanced cytotoxicity against NK targets compared to CD56 dim cells. [11][12][13] NK cell subsets have differential natural killer receptor (NKR) NK cells constitutively express receptors for monocyte-derived cytokines (monokines) and produce critical cytokines, such as IFN-␥, in response to monokine stimulation. [17][18][19][20] In the current study we examine CD56 bright and CD56 dim NK cell production of multiple cytokines-including IFN-␥, tumor necrosis factor (TNF)-␤, IL-10, IL-13, TNF-␣, and GM-CSF-in response to stimulation with monokines. We show that CD56 bright NK cells are the primary population responsible for NK cell cytokine production in response to monokines. These data support a model whereby CD56 bright a...

SummaryInterleukin 15 (IL-15) is a novel cytokine that has recently been doned and expressed. Whereas it has no sequence homology with IL-2, IL-15 interacts with components of the IL-2 receptor (IL-2R). In the present study we performed a functional analysis of recombinant IL-15 on phenotypically and functionally distinct popttlations of highly purified human natural killer (NK) cells. The CD56 b~ht subset of human NK cells constitutively expresses the high affinity IL-2R and exhibits a brisk proliferative response after the binding of picomolar amounts of IL-2. Using a proliferation assay, IL-15 demonstrated a very steep dose-response curve that was distinct from the dose-response curve for IL-2. The proliferative effects of IL-15 could be abrogated by anti-IL-2R~ (p75), but not by anti-IL-2Rc~ (p55). The proliferative effects of IL-2 on CD56bns ht NK cells could be inhibited by both antibodies. CD56 ~n NK cells express the intermediate affinity IL-2R in the absence of the high affinity IL-2R. Activation of CD56 a~ NK cells by IL-15 was similar to that of IL-2 as measured by enhanced NK cytotoxic activity, antibodydependent cdlular cytotoxicity, and NK cell production of interferon % tumor necrosis factor c~, and granulocyte/macrophage colony-stimulating factor. The IL-15-enhanced NK cytotoxic activity could be completely blocked by anti-IL-21L8 monoclonal antibody. The binding of radiolabded IL-2 and IL-15 to CD56 d~n NK cells was inhibited in the presence of anti-IL-21LB. Scatchard analysis of radiolabeled IL-15 and IL-2 binding to NK-enriched human lymphocytes revealed the presence of high and intermediate affinity receptors for both ligands. IL-15 is a ligand that activates human NK cells through components of the IL-2R in a pattern that is similar but not identical to that of IL-2. Unlike IL-2, IL-15 is produced by activated monocytes/macrophages. The discovery of IL-15 may increase our understanding of how monocytes/macrophages participate in the regulation of NK cell function.

Purpose-This randomized clinical trial tests the hypothesis that a psychological intervention can reduce emotional distress, improve health behaviors and dose-intensity, and enhance immune responses.Patients and Methods-We studied 227 women who were surgically treated for regional breast cancer. Before adjuvant therapy, women completed interviews and questionnaires assessing emotional distress, social adjustment, and health behaviors. A 60-mL blood sample was drawn for immune assays. Patients were randomly assigned to either the intervention group or assessment only group. The intervention was conducted in small patient groups, with one session per week for 4 months. The sessions included strategies to reduce stress, improve mood, alter health behaviors, and maintain adherence to cancer treatment and care. Reassessment occurred after completion of the intervention.Results-As predicted, patients receiving the intervention showed significant lowering of anxiety, improvements in perceived social support, improved dietary habits, and reduction in smoking (all P < .05). Analyses of adjuvant chemotherapy dose-intensity revealed significantly more variability (ie, more dispersion in the dose-intensity values) for the assessment arm (P < .05). Immune responses for the intervention patients paralleled their psychological and behavioral improvements. T-cell proliferation in response to phytohemagglutinin and concanavalin A remained stable or increased for the Intervention patients, whereas both responses declined for Assessment patients; this effect was replicated across three concentrations for each assay (all P < .01).Conclusion-These data show a convergence of significant psychological, health behavior, and biologic effects after a psychological intervention for cancer patients.

BACKGROUND. The question of whether stress poses a risk for cancer progression has been difficult to answer. A randomized clinical trial tested the hypothesis that cancer patients coping with their recent diagnosis but receiving a psychologic intervention would have improved survival compared with patients who were only assessed. METHODS. A total of 227 patients who were surgically treated for regional breast cancer participated. Before beginning adjuvant cancer therapies, patients were assessed with psychologic and behavioral measures and had a health evaluation, and a 60‐mL blood sample was drawn. Patients were randomized to Psychologic Intervention plus assessment or Assessment only study arms. The intervention was psychologist led; conducted in small groups; and included strategies to reduce stress, improve mood, alter health behaviors, and maintain adherence to cancer treatment and care. Earlier articles demonstrated that, compared with the Assessment arm, the Intervention arm improved across all of the latter secondary outcomes. Immunity was also enhanced. RESULTS. After a median of 11 years of follow‐up, disease recurrence was reported to occur in 62 of 212 (29%) women and death was reported for 54 of 227 (24%) women. Using Cox proportional hazards analysis, multivariate comparison of survival was conducted. As predicted, patients in the Intervention arm were found to have a reduced risk of breast cancer recurrence (hazards ratio [HR] of 0.55; P = .034) and death from breast cancer (HR of 0.44; P = .016) compared with patients in the Assessment only arm. Follow‐up analyses also demonstrated that Intervention patients had a reduced risk of death from all causes (HR of 0.51; P = .028). CONCLUSIONS. Psychologic interventions as delivered and studied here can improve survival. Cancer 2008. © 2008 American Cancer Society.