Production of interleukin-2 by YAC-1 cells stimulated with interleukin-1 and its augmentation of the natural killer activity

The production of interleukin-2 (IL-2) by YAC-1 cells stimulated with interleukin-1 (IL-1) was examined in the in vitro culture system. The IL-2 activity was detectable in the culture supernatant of YAC-1 cells stimulated with either a mouse IL-1 preparation or human purified IL-1. This activity could be detected 1 h after stimulation with IL-1. The addition of monoclonal antibody reactive with mouse IL-2 receptor completely blocked the IL-2 activity in the culture supernatant of IL-1-stimulated YAC-1 cells. Further, the culture supernatant of IL-1-stimulated YAC-1 cells augmented the NK activity in mouse spleen cells. The role of the IL-2 activity in the culture supernatant of IL-1-stimulated YAC-1 cells on augmentation of the NK activity is discussed.     

Gene expression and secretion of cytokines and cytokine receptors from highly purified CD56+ natural killer cells stimulated with interleukin-2, interleukin-7 and interleukin-12

Interleukin (IL)-2 IL-7 and IL-12 stimulate the generation of lymphokine-activated killer activity and proliferation in natural killer (NK) cells by different mechanisms. In this study, we have compared the ability of IL-2, IL-7 and IL-12 to induce expression of cytokines and cytokine receptors both at the gene and protein level. IL-2 and IL-12 stimulated the CD56⁺ NK cells to release significant amounts of soluble p55 and p75 tumor necrosis factor receptor (TNFR), whereas less amounts of soluble TNFR were detected in IL-7-stimulated cultures. The p55 and p75 TNFR mRNA were expressed in resting NK cells, and no further induction was observed after cytokine-stimulation. Compared to the effects of IL-2, IL-7 induced lower, but substantial levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) mRNA, and IL-7 was a more potent GM-CSF-inducing stimulus than IL-12. IL-12 induced higher levels of interferon-γ (IFN-γ) mRNA than did IL-2, and IL-7 only weakly influenced the IFN-γ expression. In accordance with the mRNA studies, IL-7 induced the secretion of high amounts of GM-CSF and no or low levels of IFN-γ, whereas high amounts of IFN-γ and low levels of GM-CSF were detected in supernatants from IL-12-stimulated NK cells. In conclusion, IL-2, IL-7 and IL-12 differentially regulate expression of cytokines and cytokine receptors both at the gene and protein level.     

Lymphokine-activated killer cells, natural killer cells and cytokines

In the past year, natural killer cells have been the subject of much active investigation. The analysis of the effect of cytokines on the generation, proliferation and function of natural killer cells, and the definition of the lymphokines that they produce, have been particularly important areas of research in view of their possible application in adaptive immunotherapy, combined with biological response modifiers.     

Co-stimulation of human decidual natural killer cells by interleukin-2 and stromal cells

At the late secretory phase of the menstrual cycle and in early pregnancy, the uterine mucosa is infiltrated by large numbers of natural killer (NK) cells with a distinctive phenotype (CD56bright CD16- CD3-) and large granular lymphocyte (LGL) morphology. Circulating CD56bright NK cells generally proliferate in the presence of interleukin-2 (IL-2), but it is clear that cofactors besides IL-2 are required for optimal response. In the bone marrow, this co-stimulating signal is provided by stromal cells. In the present study we observe that uterine CD56+ cells from early pregnancy decidua similarly proliferate vigorously when cultured with decidual stromal cells and a suboptimal dose of IL-2. This response is dependent on cell-cell contact, as no proliferation of decidual NK cells was observed when they were separated from stromal cells by a permeable cyclopore membrane. In addition, we have studied the expression of Bcl-2 by decidual CD56+ cells. Our results show that the microenvironment of the uterus is likely to have a significant influence on the proliferation and survival of uterine CD56+ cells.     

Adhesion of Epstein-Barr virus-positive natural killer cell lines to cultured endothelial cells stimulated with inflammatory cytokines

Chronic active Epstein-Barr virus (EBV) infection (CAEBV) is characterized by chronic recurrent infectious mononucleosis-like symptoms. Approximately one-fourth of CAEBV patients develop vascular lesions with infiltration of EBV-positive lymphoid cells. Furthermore, EBV-positive natural killer (NK)/T cell lymphomas often exhibit angiocentric or angiodestructive lesions. These suggest an affinity of EBV-positive NK/T cells to vascular components. In this study, we evaluated the expression of adhesion molecules and cytokines in EBV-positive NK lymphoma cell lines, SNK1 and SNK6, and examined the role of cytokines in the interaction between NK cell lines and endothelial cells. SNKs expressed intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) at much higher levels than those in EBV-negative T cell lines. SNKs produced the larger amount of tumour necrosis factor (TNF)-alpha, which caused increased expression of ICAM-1 and VCAM-1 in cultured human endothelial cells, than that from EBV-negative T cell lines. Furthermore, SNKs exhibited increased adhesion to cultured endothelial cells stimulated with TNF-alpha or interleukin (IL)-1beta, and the pretreatment of cytokine-stimulated endothelial cells with anti-VCAM-1-antibodies reduced cell adhesion. These indicate that the up-regulated expression of VCAM-1 on cytokine-stimulated endothelial cells would be important for the adhesion of EBV-positive NK cells and might initiate the vascular lesions.     

Down-regulation of interleukin-2 receptor expression on natural killer cells/large granular lymphocytes by interleukin-4.

It has recently been demonstrated that IL-4 inhibits IL-2 receptor expression on T cells. Studies have also shown that IL-4 can inhibit IL-2-induced natural killer cell (NK) cytotoxicity, and that IL-4 in combination with IL-2 and large granular lymphocyte (NK/LGL) cells suppresses Ig synthesis. Therefore, we examine whether IL-2 receptor expression on NK/LGL cells is affected with or without IL-4, using fluorescent receptor analysis. Our results demonstrate that IL-4 inhibits/down-regulates the expression of IL-2 receptors on either phytohemagglutinin or IL-2-stimulated NK/LGL cells.     

Dendritic cells stimulated with Actinobacillus actinomycetemcomitans elicit rapid gamma interferon responses by natural killer cells

Human immunoglobulin G2 (IgG2) responses are gamma interferon (IFN-gamma) dependent, and monocyte-derived dendritic cells (mDCs) promote IgG2 production. DCs spontaneously emerge from monocytes in cultures prepared from localized aggressive periodontitis (LagP) patients, and these patients have high levels of IgG2 that is reactive with Actinobacillus actinomycetemcomitans. These results prompted the hypothesis that an interaction between mDCs and A. actinomycetemcomitans promotes IFN-gamma production, and IFN-gamma is known to promote both immunopathology and protective IgG2. A. actinomycetemcomitans induced mDCs to produce interleukin-12 (IL-12), and the addition of A. actinomycetemcomitans and DCs to cultured peripheral blood lymphocytes elicited high levels of IFN-gamma within just 24 h. In contrast, IL-4 was not detectable although DC-derived IL-10 production was apparent. A. actinomycetemcomitans-stimulated macrophages prepared from the same monocytes lacked the ability to induce IL-12 or IFN-gamma responses. NK cells of the innate immune system were the primary source of this early IFN-gamma, although CD8 T cells also contributed some. The NK cell-derived IFN-gamma was IL-12 dependent, and A. actinomycetemcomitans-DC interactions were Toll-like receptor 4 dependent. A. actinomycetemcomitans and A. actinomycetemcomitans lipopolysaccharide (LPS) were more potent than Escherichia coli and E. coli LPS in the ability to induce DC IL-12 and IFN-gamma. The ability of A. actinomycetemcomitans-stimulated DCs to induce NK cells to rapidly produce IFN-gamma in the absence of detectable IL-4 suggests their potential for skewing responses toward Th1. This may help explain the presence of Th1-associated cytokines in gingival crevicular fluid (GCF) from LagP patients and the high levels of IgG2 in their serum and GCF that is reactive with A. actinomycetemcomitans.     

Characterization of equine natural killer and IL-2 stimulated lymphokine activated killer cell populations.

Natural killer (NK) cells are an important component of the innate immune system. Though intensively studied in humans and rodents. NK cells remain less well characterized in other species. Studies are often limited by the lack of specific cell markers; however, the mAb NK-5C6 has been suggested to recognize an evolutionarily conserved molecule on NK cells and reacts with cells from several species. This mAb was used in the current investigation to identify and characterize equine NK cells, and was found to label approximately 10% of peripheral blood lymphocytes (PBL). Two-color flow cytometry analysis identified the NK-5C6+ cell population as being CD3-CD4- and CD8-, but positive for MHC class I and LFA-1 expression. Depletion of CD3+ T cells increased the percent NK-5C6+ cells in PBL; this enriched population demonstrated a specific cytotoxic response against a major histocompatibility complex (MHC) deficient NK target cell line (K-562), but not MHC+ target cells (EqT8888). These results provide evidence for an equine NK cell population, which exhibits endogenous lytic activity and a phenotype similar to that of human and mouse NK cells. Stimulation of peripheral blood mononuclear cells (PBMC) with IL-2 promoted the development of LAK cells. These cells were predominantly CD3+ T cells, demonstrated intracellular perforin expression, and effectively lysed both K-562 and EqT8888 target cells. Hence, equine NK cells can be identified by the NK-5C6 mAb and distinguished from IL-2 stimulated LAK cells by their cytotoxic response to specific target cell lines.     

经链球菌菌体制剂OK-432刺激的树突状细胞对自然杀伤细胞增殖及功能的影响

目的:探讨经链球菌菌体制剂OK-432刺激的树突状细胞(Dendritic cells,DC)对自体自然杀伤细胞(Naturalkiller cells,NK)体外扩增和功能的影响。方法:将DC分为未成熟DC组和OK-432刺激的DC组,48小时后MTT法检测DC增殖情况,FCM检测DC表型CD80、CD83、CD86的表达情况;后将未成熟DC组和OK-432刺激的DC组分别与NK细胞以1∶1、1∶5、1∶10、1∶20、1∶40比例混合继续培养。0、2、4、6天时计算NK细胞扩增倍数;FCM检测NK细胞PFP、GraB、CD107a的表达;LDH释放法检测NK对HepG2细胞的杀伤活性。结果:OK-432(5μg/ml)使DC增殖达到最佳(30%),且能显著增强DC表型表达(P<0.05)。1∶5(OK-DC)组NK细胞扩增倍数达最大(P<0.05);1∶5(OK-DC)组能显著促进NK释放穿孔素(Pore-forming protein,PFP)、颗粒酶(Granzyme B,GraB)、CD107a(P<0.05);1∶5(OK-DC)组对HepG2细胞的杀伤活性(67.12±5.36)%达到最大(P<0.05)。结论:OK-432(终浓度5μg/ml)能促进DC增殖,并促进DC成熟;OK-DC与NK细胞共培养能以剂量依赖的方式增强NK细胞杀伤HepG2细胞功能,可能与增加NK扩增倍数和PFP、GraB、CD107a的表达有关。     

Role of interleukin-2-receptor-positive cells and natural killer cells on rejected liver grafts of rats

We explored the subpopulation and distribution of infiltrating leukocytes in rejected liver grafts using an orthotopic liver transplantation model of rats. We obtained the following results: (1) OX08- and recombinant-interleukin 2-receptor-positive cells were numerously increased in rejected grafts. (2) There was an abnormal distribution of R73-positive OX08-positive OX19-negative cells in the sinusoidal area of rejected grafts. These results suggest that R73-positive OX08-positive OX19-negative cells (natural killer cells or T cells?) have a role in the immunologic reaction in the sinusoidal area of rejected liver grafts of rats.     

Modulation of in vitro porcine natural killer cell activity by recombinant interleukin-1 alpha, interleukin-2 and interleukin-4.

Stimulation with lipopolysaccharide (LPS) initiated monocytes to produce interleukin-2 receptor light chain (p55 IL-2R). After stimulation with LPS for 48 hr, considerable quantities of soluble IL-2R were found in the supernatants of monocytes, exceeding even the amount of soluble IL-2R produced by activated T lymphocytes. Cell-associated p55 IL-2R was also increased during the first 24 hr of stimulation, after which time it remained constant. Fractionation of cells and analysis of cytoplasm, mitochondria, plasma membranes and nuclei for the presence of p55 IL-2R revealed that the main portion of receptor was present in the cytoplasm. This led to the conclusion that in monocytes cell-associated p55 IL-2R is not necessarily attached to membranes but is present in a soluble form in the cytoplasm, presumably freshly produced with the aim of being secreted. Stimulation of monocytes with pure recombinant interferon-gamma did not lead to augmentation of p55 IL-2R, as shown by enzyme-linked immunosorbent assay, binding of antibodies directed against the receptor (anti-Tac, CD25) and analysis of p55 IL-2R gene expression.     

Role of interleukin-18 in human natural killer cell is associated with interleukin-2

Human natural killer (NK) cells constitute an important cellular component of innate immunity, capable of killing infected and transformed cells. The proliferation and activation of NK cells are regulated by various cytokines. Interleukin-18 (IL-18) promotes NK cell activation; however, whether the effects of IL-18 on NK cell are associated with other cytokines is still unknown. In this study, we observed that IL-18 induced NK cell apoptosis and inhibited NK cell expansion in the presence of low concentrations of interleukin-2 (IL-2), while high concentrations of IL-2 overcame these effects of IL-18, and high concentrations of IL-2 promoted the stimulatory activity of IL-18 on NK cells. At a low concentration of IL-2, IL-18 induced NK cell apoptosis in part through activation of the FasL/Fas- and TNFα/TNFR-mediated death receptor signaling by enhancing FasL expression and inhibiting c-FLIP(long) expression. However, high concentrations of IL-2 strongly blocked IL-18-induced NK cell apoptosis through alleviating IL-18-induced FasL expression and activation of Fas-mediated death signaling and increasing anti-apoptosis molecule (Bcl-X(L)). These results reveal that the effects of IL-18 on human NK cell are associated with IL-2 concentration and suggest the importance of IL-2 level in cytokine immunotherapy.     

Role of interleukin-18 in human natural killer cell is associated with interleukin-2

Human natural killer (NK) cells constitute an important cellular component of innate immunity, capable of killing infected and transformed cells. The proliferation and activation of NK cells are regulated by various cytokines. Interleukin-18 (IL-18) promotes NK cell activation; however, whether the effects of IL-18 on NK cell are associated with other cytokines is still unknown. In this study, we observed that IL-18 induced NK cell apoptosis and inhibited NK cell expansion in the presence of low concentrations of interleukin-2 (IL-2), while high concentrations of IL-2 overcame these effects of IL-18, and high concentrations of IL-2 promoted the stimulatory activity of IL-18 on NK cells. At a low concentration of IL-2, IL-18 induced NK cell apoptosis in part through activation of the FasL/Fas- and TNFα/TNFR-mediated death receptor signaling by enhancing FasL expression and inhibiting c-FLIP_long expression. However, high concentrations of IL-2 strongly blocked IL-18-induced NK cell apoptosis through alleviating IL-18-induced FasL expression and activation of Fas-mediated death signaling and increasing anti-apoptosis molecule (Bcl-X_L). These results reveal that the effects of IL-18 on human NK cell are associated with IL-2 concentration and suggest the importance of IL-2 level in cytokine immunotherapy.     

子痫前期小鼠动物模型的NK细胞和细胞因子的变化

目的:探讨磷脂酰丝氨酸(PS)/磷脂酰胆碱(PC)诱导的先兆子痫模型小鼠中自然杀伤(NK)细胞在外周血、脾脏及子宫的数量及其表面受体的变化,同时了解外周血中的细胞因子(TGF-β、TNF-α和IFN-γ)的水平.方法:用磷脂酰丝氨酸(PS)/磷脂酰胆碱(PC)诱导小鼠出现先兆子痫(PE)样症状,流式细胞仪检测自然杀伤(NK)细胞在外周血、脾脏及子宫的数量和表面受体,酶联免疫法检测外周血中TGF-β、TNF-α和IFN-γ.结果:我们建立的PE样小鼠模型是成功的;与对照组相比,gd17.5时PS/PC组外周血和脾脏中NK细胞数目增加.gd11.5时子宫中NK细胞数目突然增加,随后逐渐降低,且在gd14.5和gd17.5时PS/PC组比对照组NK细胞数目明显减少.PS/PC组脾脏中表面受体CD122表达显著降低,而CD244、CD94及NKG2D均显著增加;子宫中所有表面受体显著降低.在gd11.5、gd14.5及gd17.5时,与对照组相比,PS/PC组外周血中TGF-β的表达水平显著增加;而TNF-α和IFN-γ表达的水平大多不发生明显变化.结论:PE可能与母胎界面处NK细胞的数量及表面受体改变有关.外周血中TGF-β的增加可能抑制子宫处NKG2D等NK细胞表面受体的表达.关于TNF-α和IFN-γ在PE样小鼠模型中的作用还需进一步研究.     

Hypothyroidism after treatment with interleukin-2 and lymphokine-activated killer cells

The development of a goiter and hypothyroidism in a 28-year-old man in whom metastatic melanoma had been treated with interleukin-2 and lymphokine-activated killer cells (LAK cells) prompted us to assess thyroid function in patients undergoing this therapy. Thirty-four patients with advanced neoplasms who had received interleukin-2 and LAK cells were followed for at least four weeks after treatment. Seven patients (21 percent) had laboratory evidence of hypothyroidism, with a decline in the serum thyroxine concentration to below normal (less than or equal to 35 nmol per liter; normal, 65 to 148), a decline in the serum free thyroxine index, and a rise in the serum thyrotropin concentration (peak values, 7.2 to 166 mU per liter; normal, 0.5 to 5.5) 6 to 11 weeks after treatment. Two patients had elevated serum thyrotropin levels before treatment, which increased further after treatment. In two patients, these abnormal values returned to normal within 10 months. All five symptomatic patients had borderline or elevated serum antimicrosomal antibody titers after treatment; two had serum antibodies to thyroglobulin. Five of the seven patients with hypothyroidism (71 percent) but only 5 of the 27 euthyroid patients (19 percent) had evidence of tumor regression (P less than 0.02). None of 11 patients treated with interleukin-2 but not LAK cells had hypothyroidism. We conclude that treatment with interleukin-2 and LAK cells can cause hypothyroidism, possibly by exacerbating preexisting autoimmune thyroiditis, and that it may be associated with a favorable tumor response.     

Synergistic activation of human natural killer cell cytotoxicity by histamine and interleukin-2

Interleukin-2 (IL-2) is recognized as a major activating signal for human natural killer (NK) cells. The presence of monocytes alters NK cell responsiveness to IL-2. Thus, while IL-2 effectively augments NK cell cytotoxicity (NKCC) in monocyte-depleted NK effector cells, it is relatively ineffective or even suppressive for NK cells in monocyte-containing, NK-cell-enriched mononuclear cell fractions. Here we report that concomitant treatment with IL-2 and the biogenic amine histamine synergistically augmented NKCC against K562 and Daudi target cells of CD3-/CD16+ human NK cells in the presence but not in the absence of monocytes. Addition of peripheral-blood monocytes, recovered by countercurrent centrifugal elutriation, to purified NK cells abrogated IL-2 induced NK cell activation, reconstituted the synergistic, NK-activating effects of histamine and IL-2, and strongly reduced baseline NKCC. The effects of histamine on baseline NKCC and on NK cell responsiveness to IL-2 were related to counteraction of monocyte-mediated NK cell suppression. By contrast, histamine did not affect baseline or IL-2-induced NKCC in mixtures of NK cells and monocytes when the latter cells were recovered after adherence. The effect of histamine on NK cell responsiveness to IL-2 was mediated by H2-type histamine receptors, as judged by mimicry exerted by the specific H2 receptor agonist dimaprit, but not by an H2-receptor-inactive derivative of this compound, N-methyldimaprit, and blocking by the H2 receptor antagonist ranitidine. Experiments in which monocytes and nonadherent NK cells were separately pretreated with ranitidine prior to histamine treatment suggested that NK-regulatory effects of histamine were mediated by H2 receptors on monocytes. Our data suggest that histamine may provide an important signal in the regulation of NK cell responsiveness to IL-2.     

Endometriosis: Secretion of interleukin-6 by human endometriotic cells and regulation by proinflammatory cytokines and sex steroids

Endometriosis is generally associated with an immuno-inflammatoryprocess that takes place in the peritoneal cavity of patients.Interleukin (IL)-6, a multifunctional cytokine involved in numerousimmunological and prolifer-ative processes, has been found athigh concentrations in the peritoneal fluid of endometriosispatients. The purpose of this study was to investigate the abilityof endometriotic cells to produce IL-6 and to assess the regulationof its secretion by proinflammatory cytokines and sex steroids.Cultures of human endometriotic cells were exposed to differentconcentrations of cytokines and sex steroid hormones for varyingperiods of time. IL-6 secretion was measured using an enzyme-linkedimmunosorbent assay. Endometriotic cells spontaneously releasedIL-6 in culture. IL-1 and tumour necrosis factor (TNF)- (0.1–100.0ng/ ml) potentiated IL-6 secretion in a time- and dose-dependentmanner. Interferon- (0.4–400 ng/ml) induced a dose-relatedincrease in IL-6 secretion and showed a synergjstic effect onthat secretion in combination with TNF- (10 ng/ ml). Eitherspontaneous or cytokine-induced IL-6 secretion was inhibitedby progesterone (10^–8–10^–5 M) and danazol(10^–6 M), whereas oestradiol (10^–8–10^–5M) had a limited inhibitory effect. The antiprogestin RU486(l0^–8–10^–4 M) antagonized the inhibitory effectsof progesterone and danazol, but showed agonist action whenused alone. These findings indicate that endometriotic tissuemay actively contribute to the biological changes observed inthe peritoneal fluid of endometriosis patients. They also providenew insights into the mechanisms of action of progesterone andthose of danazol and RU486 used in the treatment of endometriosis.     

Growth of certain myeloid leukemic cells can be stimulated by interleukin-2.

The effect of recombinant interleukin-2 (IL-2) on the proliferation of T-cell depleted leukemic blasts was evaluated in 23 patients with acute myelogenous leukemia (AML). For this purpose, the effect of IL-2 on cell growth, [3H]-thymidine incorporation into the blasts and the expression of IL-2 receptors on cell surface using T-cell depleted blasts were studied. The results showed that IL-2 stimulated [3H]-thymidine incorporation significantly in blasts of 8 out of 23 cases of AML. An IL-2 induced increase in cell number was directly demonstrated in seven out of eight IL-2 responsive patients studied. IL-2 stimulated the proliferation of blasts in monocytic lineage (M4 and M5), but not all M4/M5 leukemics responded to rIL-2. Stimulation of the growth of leukemic cells was not correlated with the expression of Tac antigen on the cell surface, but it was significantly correlated with the expression of IL-2 receptor (IL-2R) beta chain on the cell surface. These results indicate that IL-2 is an active growth factor in certain myeloid leukemia cells, especially of monocytic type.     

细胞因子诱导的杀伤细胞联合白细胞介素2治疗恶性胸腔积液

目的 观察应用细胞因子诱导的杀伤（CIK）细胞联合白细胞介素2（IL-2）治疗恶性胸腔积液的疗效.方法 收集2009年7月至2013年7月于本院肿瘤科就诊的恶性胸腔积液患者50例,随机数字表法分为治疗组（n=24）和对照组（n=26）.胸腔积液引流净后,治疗组胸腔灌注CIK细胞联合IL-2,连续3d;对照组灌注IL-2联合顺铂,隔日1次,连续3次.治疗4周后评价疗效和不良反应.结果 治疗组有效率87.50％（21/24）,完全缓解率54.17％（13/24）;对照组有效率57.69％（15/26）,完全缓解率42.31％（11/26）.与对照组比较,治疗组的完全缓解率、有效率均增加（均P＜0.05）.不良反应比较显示,治疗组发热的发生率较高,而对照组胸痛、胃肠道反应、骨髓抑制的发生率较高（均P＜ 0.05）.与治疗前比较,治疗后两组患者的Karnofsky评分均增加（均P＜0.05）.结论 CIK细胞联合IL-2胸腔灌注治疗恶性胸腔积液不良反应小,疗效确切.     

Interaction between murine natural killer cells and trypanosomes of different species.

The involvement of natural killer (NK) cells in the immunological resistance of mice to murine-specific Trypanosoma musculi was evaluated. Murine NK cells were found to be unable to kill or inhibit T. musculi or to protect recipients from infection. In addition, the ability of spleen cells from normal mice and from mice on day 3 of T. musculi infection, at the time of maximum NK augmentation, to kill Trypanosoma cruzi and Trypanosoma lewisi was evaluated. Spleen cells from normal mice displayed significant killing of both T. cruzi and T. lewisi. Furthermore, augmented spleen cells from T. musculi-infected mice were considerably more effective than normal spleen cells in killing both T. cruzi and T. lewisi. The activity of NK cells toward YAC-1 tumor target cells was inhibited in a dose-dependent fashion by either live T. musculi or extracts of T. musculi, but not by extracts of rat-specific T. lewisi. The results suggest that well-adapted protozoan parasites may be nonsusceptible to the natural cell-mediated resistance mechanisms of their hosts. Their nonsusceptibility could result from the ability to elaborate substances that either inactivate NK cells or block NK cell interaction with complementary sites on the parasite surface.