Immune response to pre-erythrocytic stages of malaria parasites

Immunization with radiation-attenuated Plasmodium spp. sporozoites induces sterile protective immunity against parasite challenge. This immunity is targeted primarily against the intrahepatic parasite and appears to be sustained long term even in the absence of sporozoite exposure. It is mediated by multifactorial mechanisms, including T cells directed against parasite antigens expressed in the liver stage of the parasite life cycle and antibodies directed against sporozoite surface proteins. In rodent models, CD8+ T cells have been implicated as the principal effector cells, and IFN-gamma as a critical effector molecule. IL-4 secreting CD4+ T cells are required for induction of the CD8+ T cell responses, and Th1 CD4+ T cells provide help for optimal CD8+ T cell effector activity. Components of the innate immune system, including gamma-delta T cells, natural killer cells and natural killer T cells, also play a role. The precise nature of pre-erythrocytic stage immunity in humans, including the contribution of these immune responses to the age-dependent immunity naturally acquired by residents of malaria endemic areas, is still poorly defined. The importance of immune effector targets at the pre-erythrocytic stage of the parasite life cycle is highlighted by the fact that infection-blocking immunity in humans rarely, if ever, occurs under natural conditions. Herein, we review our current understanding of the molecular and cellular aspects of pre-erythrocytic stage immunity.     

Natural killer lymphocytes: biology,development, and function

Natural killer (NK) lymphocytes represent the first line of defense against virally infected cells and tumor cells. The role of NK cells in immune responses has been markedly explored, mainly due to the identification of NK cell receptors and their ligands, but also through the analysis of mechanisms underlying the effects of various cytokines on NK cell development and function. A population of lymphocytes that shares function and receptors with NK cells is represented by natural killer T (NKT) cells. NKT lymphocytes are regulators of both innate and adaptive immune responses, but have also been reported to function as effector antitumor cells. The marked progress in our understanding of the biology, development, and function of NK/NKT cells has provided the basis for their potential application in tumor clinical trials.This work was presented at the first Cancer Immunology and Immunotherapy Summer School, 8–13 September 2003, Ionian Village, Bartholomeio, Peloponnese, Greece.     

γc cytokine-aided crosstalk between dendritic cells and natural killer cells together with doxorubicin induces a healer response in experimental lymphoma by downregulating FOXP3 and programmed cell death protein 1

Background aimsThe stimulatory natural killer–dendritic cell axis in the tumor microenvironment could play a critical role in stimulating cytotoxic T cells and driving immune responses against cancer.MethodsWe established a novel treatment protocol by adroitly combining chemotherapy with doxorubicin and immunotherapy with dendritic cells and natural killer cells against a highly aggressive and malignant lymphoma called Dalton's lymphoma.ResultsOur data suggest that binary application of adoptive cell therapy and chemotherapy nearly cures (95%) early-stage experimental lymphoma. In the case of mid-stage cancer, the success rate was significantly lower but still impressive (75%). Our results demonstrated that the application of combination therapy in early-stage cancer significantly reduced the tumor volume and extended the lifespan of the experimental animal in addition to reinvigorating the immune system, including restoring the effector functions of dendritic cells and natural killer cells. The novel protocol limits the metastasis of tumor cells in vascularized organs and rearms the adaptive immune response mediated by dendritic cells and CD4⁺ and CD8⁺ T cells.ConclusionsCombination therapy in the early stage alters the cytokine profile, increases interferon-γ and tumor necrosis factor-α in the serum of treated animals and downregulates programmed cell death protein 1 expression in CD8⁺ T cells. Thus, cooperative and cognitive interactions between dendritic cells and natural killer cells in addition to therapy with doxorubicin promote the immune response and tumoricidal activities against lymphoma.     

Mechanism and regulation of natural cytotoxicity. Minireview on cancer research

Natural killer (NK) cells comprise a heterogeneous population of effector cells functionally and phenotypically distinct from B cells and mature antigen-sensitive T cells, with the capacity to spontaneously lyse target cells of widely different tissue provenance in a genetically unrestricted fashion. As such they have been widely implicated in immunosurveillance against neoplastic and virus-infected cells, as well as in the homeostasis of haematopoietic differentiation and regulation of immune function. In common with cytotoxic T cells, the lytic mechanism may be resolved into several discrete stages. Target cell recognition appears to involve several chemical entities, while susceptibility is also influenced by a multiplicity of factors operative at post-recognition stages of the lytic process. NK activity is subject to both positive and negative regulation. The potentiating effects of interferons and interleukin-2, products of activated T cells, indicate a possible pathway by which adaptive immune responses may augment natural cytotoxicity under local physiological conditions. Negative regulation is mediated by certain prostaglandins and a variety of cell types including macrophages, granulocytes and thymocytes as well as subsets of peripheral blood lymphocytes.     

Invariant natural killer T cells: bridging innate and adaptive immunity

Cells of the innate immune system interact with pathogens via conserved pattern-recognition receptors, whereas cells of the adaptive immune system recognize pathogens through diverse, antigen-specific receptors that are generated by somatic DNA rearrangement. Invariant natural killer T (iNKT) cells are a subset of lymphocytes that bridge the innate and adaptive immune systems. Although iNKT cells express T cell receptors that are generated by somatic DNA rearrangement, these receptors are semi-invariant and interact with a limited set of lipid and glycolipid antigens, thus resembling the pattern-recognition receptors of the innate immune system. Functionally, iNKT cells most closely resemble cells of the innate immune system, as they rapidly elicit their effector functions following activation, and fail to develop immunological memory. iNKT cells can become activated in response to a variety of stimuli and participate in the regulation of various immune responses. Activated iNKT cells produce several cytokines with the capacity to jump-start and modulate an adaptive immune response. A variety of glycolipid antigens that can differentially elicit distinct effector functions in iNKT cells have been identified. These reagents have been employed to test the hypothesis that iNKT cells can be harnessed for therapeutic purposes in human diseases. Here, we review the innate-like properties and functions of iNKT cells and discuss their interactions with other cell types of the immune system.     

Role of natural killer cells in resistance against friend retrovirus-induced leukemia

We have previously shown that immunization with a synthetic peptide that contains a single CD4(+) T-cell epitope protects mice against immunosuppressive Friend retrovirus infection. Cells producing infectious Friend virus were rapidly eliminated from the spleens of mice that had been immunized with the single-epitope peptide. However, actual effector mechanisms induced through T-helper-cell responses after Friend virus inoculation were unknown. When cytotoxic effector cells detected in the early phase of Friend retrovirus infection were separated based on their expression of cell surface markers, those lacking CD4 and CD8 but expressing natural killer cell markers were found to constitute the majority of effector cells that lysed Friend virus-induced leukemia cells. Depletion of natural killer cells by injecting anti-asialo-ganglio-N-tetraosylceramide antibody did not affect the number of CD4(+) or CD8(+) T cells in the spleen, virus antigen-specific proliferative responses of CD4(+) T cells, or cytotoxic activity against Friend virus-induced leukemia cells exerted by CD8(+) effector cells. However, the same treatment markedly reduced the killing activity of CD4(-) CD8(-) effector cells and completely abolished the effect of peptide immunization. Although the above enhancement of natural killer cell activity in the early stage of Friend virus infection was also observed in mice given no peptide, these results have demonstrated the importance and requirement of natural killer cells in vaccine-induced resistance against the retroviral infection.     

NK cells and apoptosis

Natural killer (NK) cells are a cell of the innate immune system that play an important role in the early response to viral infections and tumours. Natural killer cells are cytolytic, and secrete cytokines that influence the developing antigen-specific immune response. In the present article the NK cell surface molecules regulating effector function, the NK cell effector mechanisms involved in apoptosis, and the role of NK cell effector mechanisms in immune responses are reviewed.     

The immune response to herpes simplex virus

Several host immune mechanisms are activated in the course of a herpes simplex virus infection. These include natural resistance mechanisms (natural killer cells and interferon), antiviral antibodies and effector CD4 and CD8 T lymphocytes. An important mechanism in the control of viral replication in epidermal cells involves the recruitment and activation of macrophages by CD4 T cells. In some instances, the action of CD4 T cells can lead to immune pathology following infection of the eye (stromal ketatitis) or central nervous system (demyelination). Despite the efficiency of the immune response in countering infection, the virus has evolved strategies to subvert the action of antibodies and complement and the detection of infected cells by cytotoxic T lymphocytes.     

Cross-talk between NKT and regulatory T cells (Tregs) in modulation of immune response in patients with colorectal cancer following different pain management techniques

Natural killer T (NKT) and regulatory T cells (Tregs) play an important role in innate immune response. Natural killer (NK) and NKT cells are indispensable factors in the body's ongoing defense against tumor development, as well as viral infection. NKT cells are a subset of T cells that shares properties of natural killer cells and conventional T cells. They are involved in innate immune responses, tumor rejection, post transplantation immunotherapy, immune surveillance and control of autoimmune diseases. They may also play both protective and harmful roles in the progression of certain autoimmune diseases, such as diabetes, lupus, atherosclerosis, and allergen-induced asthma. Immune surveillance involves the process whereby precancerous and malignant cells are recognized by the host immune system as damaged and are consequently targeted for elimination. The pharmacological management of postoperative pain in patients with malignancies uses very different techniques whose possible cytotoxic functions we still known very poor. The present study compared effects of two different postoperative pain management techniques in patients undergoing colorectal cancer surgery on the innate immunity. Our data indicate that the patients with colorectal cancer have significantly increased the percentage of Tregs and NKT cells. The values were statistically higher during epidural analgesia in comparison with intravenous analgesia, indicating that epidural pain management technique ameliorate the immune suppression after surgery.     

Effect of the joint use of BCG and antithymocyte serum on the growth of a syngeneic tumor in mice

The growth of the syngeneic tumor Acatol in BALB/c mice was retarded if the animals were pretreated with BCG or antilymphocyte serum (ATS). Combined use of BCG and ATS led to a significantly more powerful retardation as compared to the effect produced by each factor alone. Using the adoptive transfer of splenocytes from treated mice it was shown that tumor growth suppression is effected by the cell types other than T lymphocytes and macrophages. It is probable that the effector cells within the given system are K cells and natural killer cells. The results attest to a possibility of search for a two-directional action on the immune system of the tumor host, which would stimulate antitumor effector cells and inhibit the activity of suppressors, particularly that of T suppressors.     

Human NK cells: From development to effector functions

NK cells are the major lymphocyte subset of the innate immune system that mediates antiviral and anti-tumor responses. It is well established that they develop mechanisms to distinguish self from non-self during the process of NK cell education. Unlike T and B cells, natural killer cells lack clonotypic receptors and are activated after recognizing their target via germline-encoded receptors through natural cytotoxicity, cytokine stimulation, and Ab-dependent cellular cytotoxicity. Subsequently, they utilize cytotoxic granules, death receptor ligands, and cytokines to perform their effector functions. In this review, we provide a general overview of human NK cells, as opposed to murine NK cells, discussing their ontogeny, maturation, receptor diversity, types of responses, and effector functions. Furthermore, we also describe recent advances in human NK cell biology, including tissue-resident NK cell populations, NK cell memory, and novel approaches used to target NK cells in cancer immunotherapy.     

CXCR3 ligands: redundant, collaborative and antagonistic functions

CXCR3 is a chemokine receptor that is rapidly induced on na?ve T cells following activation, and preferentially remains highly expressed on type-1 helper (Th1)-type CD4(+) T cells, effector CD8(+) T cells and innate-type lymphocytes, such as natural killer (NK) and NKT cells. CXCR3 is activated by three interferon (IFN)-γ-inducible ligands CXCL9 (monokine induced by gamma-interferon), CXCL10 (interferon-induced protein-10) and CXCL11 (interferon-inducible T-cell alpha chemoattractant). Although some studies have revealed that these ligands have redundant functions in vivo, other studies have demonstrated that the three CXCR3 ligands can also collaborate and even compete with each other. Differential regulation of the three ligands at specific times in defined anatomically restricted locations in vivo likely participates in the fine control of T-cell trafficking over the course of an immune response. Among the differences in regulation, CXCL10 is induced by a variety of innate stimuli that induce IFN-α/β as well as the adaptive immune cell cytokine IFN-γ, whereas CXCL9 induction is restricted to IFN-γ. In this review, we will discuss how the balance, timing and pattern of CXCR3 ligand expression appears to regulate the generation of effector T cells in the lymphoid compartment and subsequent migration into peripheral sites of Th1-type inflammation in which the CXCR3 ligands also then regulate the interactions and migratory behavior of effector T cells in an inflamed peripheral tissue.     

Human antigen-presenting cells respond differently to gut-derived probiotic bacteria but mediate similar strain-dependent NK and T cell activation

The intestinal microbiota is essential for homeostasis of the local and systemic immune system, and particularly strains of lactic acid bacteria and Escherichia coli have been shown to have balancing effects on inflammatory conditions such as allergy and inflammatory bowel disease. However, in vitro assessment of the immunomodulatory effects of distinct strains may depend strongly on the cell type used as a model. To select the most appropriate model for screening of beneficial bacteria in human cells, the response to strains of intestinal bacteria of three types of antigen-presenting cells (APC) was compared; blood myeloid dendritic cells (DC), monocyte-derived DC and monocytes, and the effector response of natural killer cells and na?ve T cells was characterized. Maturation induced by gut-derived bacteria differed between APC, with blood DC and monocytes responding with the production of IL-6 and tumour necrosis factor-alpha to bacteria, which elicited mainly IL-10 in monocyte-derived DC. In contrast, comparable IFN-gamma production patterns were found in both natural killer cells and T cells induced by all bacteria-matured APC. An inhibitory effect of certain strains on this IFN-gamma production was also mediated by all types of APC. The most potent responses were induced by monocyte-derived DC, which thus constitute a sensitive screening model.     

Induction of autoreactive CD8+ cytotoxic T cells during Theiler's murine encephalomyelitis virus infection: implications for autoimmunity

Theiler's murine encephalomyelitis virus (TMEV) belongs to the family Picornaviridae and causes demyelinating disease in the spinal cords of infected mice. Although immune responses have been shown to play an important role in demyelination, the precise effector mechanism(s) is unknown. Potentially autoreactive cytotoxic cells could contribute to the destruction. We tested whether an autoreactive cell induced by TMEV infection mediated cytotoxicity by using a 5-h (51)Cr release assay in SJL/J mice. Spleen cells from TMEV-infected mice were stimulated with irradiated TMEV antigen-presenting cells and used as effector cells. The effector cells differed from conventional cytotoxic T cells since these cells could kill both TMEV-infected and uninfected syngeneic or semisyngenic cell lines (PSJLSV and BxSF11gSV) but could not kill an allogeneic cell line (C57SV). The TMEV-induced autoreactive cells were also different from conventional natural killer (NK) cells or lymphokine-activated killer (LAK) cells, because they could kill neither NK cell-sensitive YAC-1 nor NK cell-resistant P815 and EL4 cells. Induction of autoreactive cells was not detected in vaccinia virus infection. The autoreactive killing required direct cell-to-cell contact and was mediated by a Fas-FasL pathway but not by a perforin pathway. The phenotype of the killer cells was CD3(+) CD4(-) CD8(+). Intracerebral inoculation of the effector cells into naive mice caused meningitis and perivascular cuffing not only in the brain parenchyma but also in the spinal cord, with no evidence of viral antigen-positive cells. This is the first report demonstrating that TMEV can induce autoreactive cytotoxic cells that induce central nervous system pathology.     

The role of Th17 cytokines in primary mucosal immunity

The T helper type 17 (Th17) lineage of CD4+ T-cells produce several effector molecules including IL-17A, IL-17F, IL-21, and IL-22. In addition to CD4+, αβ T-cells, these cytokines can be produced by natural killer and γδ T-cells. These effector cytokines can be produced rapidly upon infection at mucosal sites and evidence to date strongly implicates that this arm of the immune system plays a critical role in mucosal immunity to many extracellular pathogens. Moreover these cytokines can also coordinate adaptive immunity to some intracellular pathogens. In this review, we will highlight recent progress in our understanding of these cytokines, and mechanisms of their effector function in the mucosa.     

Human natural killer cells and cytotoxic T lymphocytes require cell surface carbohydrate determinants for lytic function

Cloned and uncloned populations of natural killer (NK) cells and cytotoxic T lymphocytes (CTL) were treated with tunicamycin, an antibiotic that inhibits N-linked glycosylation, in order to study the potential role of cell surface carbohydrate determinants in lytic function. It is shown that tunicamycin-treated NK and CTL effector cells lose killer function in a dose-dependent manner. This effect is reversible; cells washed free of tunicamycin begin to recover their killer activity within 2 to 3 days after initial treatment. Conjugate experiments indicate that killer-target cell binding is not affected by tunicamycin treatment of the NK cells. It is also shown that tunicamycin treatment of target cells does not significantly affect their ability to be lysed by NK or CTL effector cells. These studies provide evidence that carbohydrate determinants are important in the lytic mechanism of both CTL and NK cells, rather than in specific effector-target cell binding.     

Imbalance of peripheral B lymphocytes and NK cells in rheumatoid arthritis

The study was focused on several cellular immune disorders correlated with the imbalance between peripheral blood B lymphocytes and NK cells in severe rheumatoid arthritis. By flow cytometry we calculated the proportions of T, T helper, T cytotoxic/suppressor, B lymphocytes and natural killer cells in peripheral blood. The mitogen-induced proliferation of peripheral lymphocytes was measured by tritium-labeld uridine incorporation. Experimental data highlight a connection between annomal values of the B to natural killer cells ratio and disorders of the peripheral mononuclear cells concentration. We also showed that the polyclonal proliferation capacity of peripheral lymphocytes in rheumatoid arthritis is solely related to the B to natural killer cells ratio or to the natural killer cells proportion. The study reveals a potential role of the imbalance between proportions of peripheral B lymphocytes and natural killer cells in the immune pathogenesis of rheumatoid arthritis, thus pointing out an interrelation between the adaptive and innate immune systems.     

The role of nitric oxide in inflammatory reactions

Nitric oxide (NO) was initially described as a physiological mediator of endothelial cell relaxation, an important role in hypotension. NO is an intercellular messenger that has been recognized as one of the most versatile players in the immune system. Cells of the innate immune system--macrophages, neutrophils and natural killer cells--use pattern recognition receptors to recognize the molecular patterns associated with pathogens. Activated macrophages then inhibit pathogen replication by releasing a variety of effector molecules, including NO. In addition to macrophages, a large number of other immune-system cells produce and respond to NO. Thus, NO is important as a toxic defense molecule against infectious organisms. It also regulates the functional activity, growth and death of many immune and inflammatory cell types including macrophages, T lymphocytes, antigen-presenting cells, mast cells, neutrophils and natural killer cells. However, the role of NO in nonspecific and specific immunity in vivo and in immunologically mediated diseases and inflammation is poorly understood. This Minireview will discuss the role of NO in immune response and inflammation, and its mechanisms of action in these processes.     

Intravascular infiltrates and organ-specific inflammation in malaria pathogenesis

Malaria infects 5-10% of humanity and causes around two million deaths annually, mostly in children. The disease is of significant interest to immunologists, as acquired host immunity can limit the clinical impact of infection and partially reduces parasite replication; however, immunological reactions also contribute significantly to pathogenesis and fatalities. This review addresses the view that immunopathology in severe malaria arises predominantly from intravascular lesions resulting from a pathogen-initiated cascade of activated immune effector and regulatory cells infiltrating the vascular beds of diverse target organs, including bone marrow, spleen, brain, placenta and lungs. The main feature distinguishing these processes from classical cellular inflammation is the absence of extravasation, resulting from the intravascular location of the pathogen. Clinical and epidemiological observations combined with experimental infections in animal models suggest that parasite 'molecular patterns' or toxins cause cytokine and chemokine enhancement of infiltrates, composed of macrophages, neutrophils, natural killer (NK) cells, invariant natural killer T (iNKT) cells, gamma/delta T cells and both CD4(+) and CD8(+) effector T cells, leading to local vascular and organ derangement. Diverse pattern recognition and NK receptors crucially regulate these responding cell populations. Thus, innate immune mechanisms lie at the heart of this massive global public health problem.