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At least 1,387 records · Page 77Linked to original sources
PubMed1998

Dynamics of intra-hepatic lymphocytes in chronic hepatitis C: enrichment for Valpha24+ T cells and rapid elimination of effector cells by apoptosis.

Chronic viral hepatitis is characterized by a dramatic lymphocyte infiltrate in the liver. Although it is one of the most common chronic inflammatory diseases in humans, little information is available on the functional state of these intra-hepatic lymphocytes (IHL). To address this issue, we have optimized cytofluorimetric techniques to assess directly ex vivo the functions, dynamics and repertoires of IHL isolated from biopsies of patients with chronic hepatitis C. We estimate that 1% of the total body lymphocytes infiltrate the inflamed liver and find that, at variance with peripheral blood lymphocytes (PBL) isolated from the same patients, most IHL display an activated phenotype and produce Th1 type lymphokines when stimulated in vitro. Virtually all IHL are found in the G0/G1 state of the cell cycle, while a sizeable percentage of them is undergoing programmed cell death in vivo, as detected by the TUNEL assay performed on freshly isolated cells. In contrast again to PBL from the same patients, IHL show a preferential compartmentalization of NK and TCRgamma/delta+ cells, and a remarkable (up to 20-fold) enrichment for Valpha24+ T cells. Together our data suggest that in a liver injured by chronic hepatitis C, most IHL are pro-inflammatory activated cells which are highly enriched for effectors of innate resistance. These IHL do not undergo clonal expansion in the liver but rather display effector function and die in situ at a high rate, suggesting that maintenance of the IHL pool is dependent on continuous migration from extra-hepatic sites.

Antigens, CD1↗
PubMed1999

Relaxin favors the development of activated human T cells into Th1-like effectors.

Differentiation of naive CD4+ helper T (Th) cells into Th1 or Th2 effectors, as characterized by their opposite pattern of cytokine production, can be influenced by several factors, including hormones. In this study, we demonstrate that porcine relaxin, at concentrations ranging from 10(-10) to 10(-6) M, favors the in vitro development of human antigen-specific T cells into Th1-like effectors and enhances both IFN-gamma mRNA expression and IFN-gamma production by established human T cell clones. The promoting effect of relaxin on the development of IFN-gamma-producing cells was not due to a relaxin-induced release of IL-12 and/or IFN-alpha by antigen-presenting cells. These results suggest that relaxin may contribute to the regulation of the immune homeostasis during pregnancy and may also play some role in counteracting Th2-dominated disorders.

Animals↗
PubMed1989

Association of increased lytic effector cell function with high estrogen receptor levels in tumor-bearing patients with breast cancer.

Tumor-bearing patients with breast cancer were assayed for their natural killer (NK) cell activity and for the function of activated cytotoxic T-cells, as assessed by lectin-dependent cellular cytotoxicity (LDCC). Tumor-bearing patients with breast cancer had a significant increase in NK activity and in LDCC, as compared with healthy control individuals. Although the enhanced NK cell activity and LDCC were closely associated with high levels (greater than 31 fmol/mg) of estrogen receptor (ER) content in the primary tumor, no other clinical or histologic correlation between the increase in either parameter of cytotoxic effector cell function could be found. Thus, ER levels greater than 31 fmol/mg might be associated with increased cytotoxic effector cell function in tumor-bearing patients with breast cancer.

Breast Neoplasms↗
PubMed2000

The enhanced antigen-specific production of cytokines induced by pertussis toxin is due to clonal expansion of T cells and not to altered effector functions of long-term memory cells.

Pertussis toxin (PT) has been shown to act as an adjuvant that enhances the production of both Th1 and Th2 cytokines to coinjected protein antigens. It has remained unresolved, however, how PT affects the clonal sizes, long-term effector functions, and Th1/Th2/Th0 differentiation of the T cell responses induced. We have studied the effects of PT on the development of the CD4(+) T cell response to a prototypic antigen, hen eggwhite lysozyme (HEL). HEL injection with incomplete Freund's adjuvant (IFA) resulted in an IFN-gamma(-)/IL-5(+) Th2 recall response. In comparison, co-administration of PT with HEL:IFA enhanced the frequencies of IL-5-producing T cells up to eightfold, and induced the differentiation of high frequencies of IFN-gamma-producing CD4(+) T cells. The results showed that the IFN-gamma and IL-5 produced, originated from clonally expanded Th1 and Th2, but not Th0 cells, and that the effector functions of long-term memory cells were unaffected. Adoptive transfer experiments suggested that PT mediated these effects via activation of APC, not by acting on the T cells directly. The effects of PT on the developing T cell response required the presence of the holotoxin (A- and B-subunit); the individual subunits did not show adjuvant effects. The data suggest that PT enhanced cytokine production by promoting differentiation and vigorous clonal expansion of Th1 and Th2 cells via activation of APC.

Animals↗
PubMed2000

CD4+Ki67+ lymphocytes in HIV-infected patients are effector T cells accumulated in the G1 phase of the cell cycle.

Entry into the cell cycle represents a fundamental step before generating an effector immune response. The relationship between the cell cycle and antigen-driven T cell response remains, however, poorly understood in virus infection, including HIV. We have identified a critical fraction of CD4+CD45RO+ memory T lymphocytes that express the Ki67 antigen in chronically HIV-infected patients. A high accumulation of Ki67 protein is detected in CD4+CD45RO+Ki67+ cells that are in the G1 phase of the cell cycle (92 ¿ 5 %) but not in S and G2 + M phases, in contrast to normal individuals. Of these cells, 20 - 60 % are spontaneously producing IL-2 and IFN-, unlike CD4+CD45RO+ that do not express Ki67. In addition, HIV-p24 antigen is detectable only in a small fraction CD4+Ki67+ cells. In conclusion, CD4+Ki67+ lymphocytes are circulating effector cells accumulated in the G1 phase of the cell cycle and may be involved in the immune surveillance during HIV infection.

Antiretroviral Therapy, Highly Active↗
PubMed2002

ICOS and CD28 reversely regulate IL-10 on re-activation of human effector T cells with mature dendritic cells.

With newly generated ICOS-ligand (ICOS-L)-specific monoclonal antibodies we determined that human Langerhans cells in situ express similar levels of ICOS-L, CD80, and CD86, compared to immature dendritic cells (DC) derived from monocytes in vitro. Maturation of DC strongly up-regulated CD80 and CD86 but did not significantly change ICOS-L levels. On coculture of "naive"CD4(+) T cells with mature DC in the presence of superantigen, ICOS was highly up-regulated on T cells, but played only a secondary role in the CD28-dominated release of TNF-alpha and IFN-gamma, and did not participate in the induction of IL-2. Cocultures of "effector" CD4(+) T cells with mature DC revealed CD28 as the driving force for the secretion of IL-2, IFN-gamma, IL-6, and IL-13, with no apparent contribution of ICOS. In contrast, the release of IL-10 was differentially regulated. Interaction of ICOS with ICOS-L strongly promoted IL-10 secretion, whereas the CD28/B7 pathway acted as a potent attenuator of IL-10 release. Our data thus indicate a selective regulation of IL-10 secretion by ICOS on re-activation of effector T cells with professional antigen-presenting cells (bearing CD80 and CD86) in lymphoid tissue.

Abatacept↗
PubMed1989

Mast cells: immunologically specific effectors and potential sources of multiple cytokines during IgE-dependent responses.

Mast cells are critical effectors in many IgE-dependent responses, and the numbers and phenotype of certain mast cell populations can be influenced, through IL-3 and IL-4, by the same T cells that regulate IgE production. However, IgE can interact with cells other than mast cells, and different mast cell populations express significant variation in multiple important aspects of their phenotype, including mediator content and responses to cytokines and stimuli of activation. As a result it may be difficult to define the unique contributions of mast cells to IgE-dependent reactions. One approach for analysing the roles of various mast cell populations in individual biological responses is to attempt to elicit these reactions in mice in which the presence or absence of specific mast cell populations can be regulated experimentally. We have used genetically mast cell-deficient and mast cell-reconstituted mice to demonstrate that mast cells provide essential effector function in certain IgE-dependent responses involving the skin, stomach or lungs but are not necessary for the pulmonary alterations and death associated with active anaphylaxis. Similar approaches can be used to investigate the biological significance of the production, by mast cells stimulated with IgE and specific antigen, of cytokines similar or identical to IL-1, IL-3, IL-4, IL-5, IL-6, TNF-alpha/cachectin, IFN-gamma, GM-CSF, JE, MIP-1 alpha, MIP-1 beta and TCA3.

Animals↗
PubMed1987

Immunoultrastructural studies of human NK cells: II. Effector-target cell binding and phagocytosis.

The binding of NK cells to a target cell appears to be a necessary step for NK cell-mediated cytolysis. In this report, we demonstrated effector-target binding by immunoelectron microscopy by using monoclonal antibodies against NK cells (Leu-7, Leu-11a) and T-cell subsets (Leu-2a/T8, Leu-3a/T4). The surfaces of NK and K562 cells were characterized by antitransferrin receptor antibody and various lectins. In addition, the controversial phagocytic activity of NK cells was studied by incubation of peripheral blood mononuclear cells with opsonized Staphylococcus aureus and labeling with anti-Leu-7 or anti-Leu-11a antibody. Results showed that only Leu-11a+ cells displayed a broad cell-to-cell contact with the target by a shallow intercellular interdigitation of cytoplasmic projections, while Leu-7+, Leu-2a+, or Leu3a+ cells showed only a partial contact with target without interdigitation. The Leu-11a+ cells were frequently observed in small clusters and in close association with monocytes. Cluster formation and association with monocytes were not observed in other NK and T-cell immunophenotypes. In Leu-11a+ cells conjugated with target cells, membrane-bound granules, small vesicles, parallel tubular arrays, Golgi apparatus, endoplasmic reticulum, and small vacuoles were evident and concentrated toward the target. The surface of NK cells was intensely stained for glycoprotein by chromic acid-phosphotungstic acid, whereas target cells were not stained. Transferrin receptors were stained only on the surface of target cells. Only the lectins RCA and UEA labeled the surfaces of both NK and target cells. Phagocytic vacuoles containing cell debris or fragments and ingested bacteria were found in the cytoplasm of Leu-11a+ cells but not in Leu-7+ cells. NK cells were also found within the cytoplasm of K562 target cells. All these findings suggest that Leu-11a+ cells are the true functional NK cells involved in NK cell-mediated cytolysis, phagocytosis, and emperipolesis. Therefore, the NK cell is probably "a phagocyte in lymphocyte's clothing." The presence of peroxidase in the small vesicles of NK cells and endocytotic vesicles of target cells at the effector-target contact area indicates that cytolytic enzymes or factors derived from NK cells may be transported into the target by endocytosis.

Antibodies, Monoclonal↗
PubMed2004

Effector function of type II collagen-stimulated T cells from rheumatoid arthritis patients: cross-talk between T cells and synovial fibroblasts.

OBJECTIVE: To investigate the effector function exerted by type II collagen (CII)-stimulated T cells on rheumatoid arthritis (RA) fibroblast-like synoviocytes (FLS), and to determine their contribution to RA pathogenesis. METHODS: We used enzyme-linked immunosorbent assays to measure the levels of interleukin-15 (IL-15), tumor necrosis factor alpha (TNFalpha), and IL-18 production by FLS that were cocultured with antigen-activated T cells. Likewise, we analyzed the levels of interferon-gamma (IFN gamma) and IL-17 production by RA T cells coincubated with FLS. To investigate the cross-talk between CII-stimulated T cells and RA FLS, we examined the effect of using a transwell membrane to separate T cells and FLS in a culture chamber, as well as the effect of adding an antibody to block CD40 ligation. RESULTS: The levels of IL-15, TNF alpha, IFN gamma, and IL-17 were all significantly increased in the serum of RA patients compared with normal control serum. Among the patients, the group with a stronger T cell proliferation response to CII showed higher levels of these inflammatory mediators. When coincubated with RA FLS, these T cells induced the production of IL-15, TNF alpha, and IL-18 by FLS with an intensity that increased in proportion to the duration of CII stimulation. T cells, in turn, responded to FLS stimulation by secreting higher amounts of IL-17 and IFN gamma in coculture. Interestingly, T cells that were activated by CII for longer periods of time showed stronger induction of these cytokines. The cross-talk between T cells and FLS appeared to require direct cell-cell contact as well as CD40 ligation, at least in part. CONCLUSION: Through repeated stimulation by CII, RA synovial T cells became trained effector cells that induced the production of proinflammatory mediators by FLS, while in the process the T cells becoming more sensitized to the activation signal from FLS.

Adult↗
PubMed2005

Tissue trafficking patterns of effector memory CD4+ T cells in rheumatoid arthritis.

OBJECTIVE: Clonal populations of CD4+,CD28- T cells accumulating in rheumatoid arthritis functionally resemble end-differentiated, nondividing, short-lived effector memory cells that reside in peripheral tissues. We undertook this study to examine the tissue niche for CD4+,CD28- T cells and the signals regulating their survival and tissue homing patterns. METHODS: Chemokine receptor expression on CD4+,CD28- T cell clones and peripheral blood lymphocytes was assessed by multicolor cytometry. In vitro chemotaxis and transendothelial migration were examined in a Transwell system. In vivo tissue-homing patterns were established by adoptively transferring fluorescence-labeled T cell clones into SCID mice engrafted either with rheumatoid synovium or with human lymph nodes. RESULTS: CD4+,CD28- T cell clones adoptively transferred into human tissue-SCID mouse chimeras infiltrated rheumatoid synovium but preferentially homed to lymph nodes. Such T cells coexpressed the chemokine receptors CCR7, CCR5, and CXCR4 and migrated in response to both inflammatory chemokines (CCL5) and homing chemokines (CXCL12). T cell receptor crosslinking abrogated chemotactic responsiveness. In contrast, interleukin-12 stimulation induced the up-regulation of CCR5 and a shift in the in vivo homing pattern away from the lymph nodes toward the inflamed synovium. CONCLUSION: CD4+,CD28- T cells resemble both short-lived effector memory cells and long-lived central memory cells, and they find a niche both in inflamed synovium and in lymph nodes. Nonspecific cytokine stimulation, not antigen recognition, triggers the transition from the lymph node to the synovium. By maintaining CCR7 expression, these end-differentiated T cells can home to lymphoid organs, enhance their survival, support clonal expansion, and perpetuate autoreactivity.

Adoptive Transfer↗
PubMed1975

Recruitment of effector lymphocytes by initiator lymphocytes: role of a trypsin-sensitive membrane component.

In earlier studies we found that initiator T lymphocytes sensitized in vitro against fibroblasts were able to recruit immunospecific effector T lymphocytes in vivo in syngeneic mice. In the present study, to investigate the possible function in effector cell recruitment of sensitizing antigens passively adsorbed onto the initiator cell membrane, we treated the initiator lymphocytes with trypsin. We found that trypsin inhibited recruitment. However, the initiator cells spontaneously recovered their recruiting ability after incubation in vitro for 4 h in the absence of contact with sensitizing antigens. Recovery could be blocked by cycloheximide. Hence, it appears that recruitment depends on the intrinsic metabolic function of the initiator lymphocytes and is not due merely to passively-adsorbed antigen carried over into the recipient mouse.

Animals↗
PubMed1976

Recruitment of effector lymphocytes by initiator lymphocytes. In vivo migration of in vitro sensitized initiator T lymphocytes.

We previously found that mouse T lymphocytes sensitized in vitro against allo- or syngeneic fibroblasts, upon injection into syngeneic recipients, do not themselves differentiate into effector cells, but recruit effector T lymphocytes within the draining lymph nodes. As a result of sensitization, these initiator lymphocytes acquire a trypsin-sensitive membrane property which is necessary for recruitment. We now report studies on the in vivo migratory behavior of initiator lymphocytes following sensitization. We injected 51Cr-labeled initiator lymphocytes into recipient footpads and found significantly increased migration of sensitized cells to the draining popliteal lymph node (PLN) during the first day. By amputation of the foot at various times, we showed that migration during the first 12-24 hours was critical for subsequent recruitment. Trypsin treatment of initiator lymphocytes abolished this accelerated migration. Lymphocytes triggered nonspecifically by Con A migrated to the PLN like antigen-sensitized cells. We also compared the migration of injected lymphocytes from the footpad to the PLN in graft-versus-host and host-versus-graft reactions, and found these reactions to differ both from each other and from recruitment in terms of lymphocyte migration. These findings are discussed in terms of the physiology of the cell-mediated immune response and the notion of peripheral sensitization.

Animals↗
PubMed1975

T cell proliferation in the mixed lymphocyte culture does not necessarily result in the generation of cytotoxic T effector cells.

It was tested whether T lymphocytes, when stimulated in vitro by M locus-coded lymphocyte activating determinants (LAD), are able to mediate cytotoxic effector functions. The assay for cytotoxicity included both the use of purified appropriate target cells (i.e. purified lipopolysaccharide blasts) as well as the use of phytohemagglutinin dependent cytolysis as a model for detecting cytotoxic T lymphocytes (CTL). Although strong proliferative responses were obtained in the mixed lymphocyte culture, the T cell blast generated did not display any detectable cytotoxic effector function. Thus, it is concluded that LAD, at least in the M locus-dependent system, do have the capacity to induce T cell proliferation but do not induce CTL.

Animals↗
PubMed1976

Lymphocyte-mediated cytotoxicity against tumor cells. III Differentiation of concanavalin A-activated cytotoxic effector cells.

The maturation of selected T cell responses in the lymphoid organs of irradiated CBA mice was followed after adoptive transfer of syngeneic fetal liver cells. Mitogenic responsiveness to phytohemagglutinin (PHA) and concanavalin A (Con A) was found to reach control values 3 weeks after reconstitution in the thymus, spleen, and lymph node, of fetal liver repopulated animals. Spleen and lymph node cell reactivity in mixed lymphocyte culture reactions required 6 weeks to reach significant values. However, the ability of spleen cell suspensions to be activated by Con A into cytotoxic effector lymphocytes appeared after only 2 to 3 weeks. It is concluded that two functionally distinct T cell subpopulations exist in the spleen, one which can be activated into cytotoxic effector lymphocytes by Con A, and one which responds to alloantigens by DNA synthesis.

Animals↗
PubMed1981

Demonstration of T15 idiotype-positive effector and suppressor T cells for phosphorylcholine-specific delayed-type hypersensitivity response in CBA/N or (CBA/N X BALB/c)F1 male mice.

Subcutaneous immunization of CBA/N or (CBA/N X BALB/c)F1 (NBF1) male mice, which were defective in phosphorylcholine (PC)-specific humoral antibody response, with PC-conjugated syngeneic spleen cells induced a PC-specific delayed-type hypersensitivity (DTH) response, while intravenous administration of the same cells induced PC-specific suppressor T cells for the DTH response. Treatment of PC-specific effector or suppressor T cells for the DTH response induced in NBF1 male mice with anti-T15 idiotypic antibody inactivated effector or suppressor functions of these T cells implying that PC-specific T cells in NBF1 mice expressed T15 idiotypic determinants on their surface. Enrichment of PC-specific suppressor T cells was also shown by employing anti-T15 antibody-coated dishes.

Animals↗
PubMed1982

Autoimmune effector cells. II. Transfer of experimental allergic encephalomyelitis with a subset of T lymphocytes.

This study was conducted to further characterize the effector cells of experimental allergic encephalomyelitis (EAE) which are activated in vitro when spleen cells from Lewis rats previously immunized with myelin basic protein and adjuvant are cultured with antigen prior to transfer to syngeneic recipients. The effector cells were isolated on discontinuous Percoll gradients in the cell fraction that floated on Percoll with a buoyant density of 1.067 kg/l. These cells (designated fraction 1) transferred EAE and incorporated [3H]dThd in culture. Fraction 1 was enriched for T cells when evaluated with monoclonal anti-rat T cell serum W3/13 and deficient in Ig+ cells; approximately 33% were positive with monoclonal anti-rat T cell serum W3/25. In contrast, the small, nonproliferating cells found in higher density Percoll fractions did not transfer EAE. When fraction 1 was recultured in the presence of basic protein and interleukin 2 for 72 h, these cells retained the ability to transfer EAE. Moreover, these recultured cells exhibited an increase in the W3/25 antigen and a decrease in the W3/13 marker. It was concluded that a subset of T cells which bear the W3/25 marker is involved in the transfer of EAE.

Animals↗
PubMed1986

Effector functions and specificities of normal murine T cells stimulated by syngeneic blasts.

Large numbers of syngeneically stimulated T cells are easily obtained by stimulation of splenic T cell populations with irradiated lipopolysaccharide (LPS) blasts. Thus, proliferative T cell responses were obtained after stimulation with allogeneic LPS blasts, concanavalin A (Con A) blasts, normal spleen cells or peritoneal macrophages while only LPS and Con A blasts were competent syngeneic stimulators. The cytolytic activity of T cells stimulated with allogeneic LPS blasts was H-2 specific, while that of T cells stimulated with syngeneic LPS blasts was often completely nonspecific, and higher for LPS than for Con A blast target cells. In other experiments, "self" H-2K- and I-A-specific cytotoxic T cells were obtained, without apparent reasons for the development of either type of cytolytic cells. Stimulation of Lyt-2- T cells with syngeneic LPS blasts led to the generation of T helper effector cells which induced normal B cell proliferation in an H-2 restricted manner. This restriction was over-come, the proliferative responses were augmented and plaque-forming cell responses generated, through addition of Con A to the cultures. The results imply the ability of B blasts to induce stimulation of syngeneic T cells, and generation of effector cells displaying cytolytic and helper activity. This phenomenon might play a role in the regulation of the immune system.

Animals↗
PubMed1986

Role of the major histocompatibility complex in targeting effector T cells into a site of virus infection.

Bone marrow radiation chimeras have been used as virus-infected, cyclophosphamide-suppressed recipients to analyze the major histocompatibility complex (MHC) restriction constraints on the adoptive transfer of lymphocytic choriomeningitis by immune T cells. The basic protocol employed [(A X B)F1----(A X C)F1] chimeras, where A, B, C are different MHC haplotypes, and the establishment of appropriate chimerism was measured by the capacity of, for instance, the transferred A, T cells to generate MHC-restricted, virus-specific cytotoxic T lymphocytes (CTL) in the spleen of the [(A X B)F1----(B X C)F1] recipients. The experiments show quite clearly that maximal inflammatory process is only induced when donor bone marrow, irradiated recipient and transferred T cells share at least one MHC haplotype. Compatibility of the T cells and the radiation-resistant phenotype alone in, for instance, transfer of C immune lymphocytes into [(A X B)F1----(B X C)F1] recipients produced little inflammation if the chimeras had been established for at least 10 weeks. These results are compatible with a model which proposes that the transferred T cells first replicate in MHC-compatible lymphoid tissue and are then targeted onto the appropriate MHC plus virus expressed on cells in the blood-cerebrospinal fluid (CSF) barrier. An alternative postulate, that all that is required for the development of inflammatory process is MHC-restricted T cell replication in lymphoid tissue, with subsequent nonspecific localization to the central nervous system (CNS), was explored by transferring B, immune T cells into [(A X B)F1----A] recipients. The finding was that H-2b effectors did not cause any meningitis in [H-2kXb F1----H-2k] recipients, though potent H-2b-restricted CTL were generated in the spleens of comparable chimeras. However, in the H-2k immune----[H-2kXbF1----H-2b] transfer there was evidence of moderate inflammation that was about 9 times less severe than that caused by the H-2b effectors in comparable recipients. This indicates that, for maximal inflammatory process to occur, the T cells must encounter MHC-compatible, virus-infected cells in the CNS, with the effect being absolute in one strain combination and partial in another. Possible mechanisms underlying this divergence are discussed.

Animals↗