ATGAM versus OKT3 induction therapy in cadaveric kidney transplantation: patient and graft survival, CD3 subset, infection, and cost analysis.
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Adolescent↗
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Results for “CD3 Complex”
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Naive CD4 T cells inhibit CD28-costimulated R5 HIV replication in memory CD4 T cells.
Stimulation with antibodies to CD3 and CD28 coimmobilized on beads can be used to significantly expand T cells ex vivo. With CD4 T cells from HIV-infected patients, this expansion usually is accompanied by complete suppression of viral replication, presumed to be caused by down-regulation of the viral coreceptor CCR5 and up-regulation of CCR5 ligands. Here we show that this suppression occurs in total CD4 T cells acutely infected with R5 HIV, but not in purified CD62L(-) memory CD4 T cells. The lack of complete suppression in these memory cells, typically comprising 10-40% of total CD4 T cells, occurs despite high levels of CCR5 ligand secretion and down-regulation of CCR5. Significantly, adding back naive or CD62L(+) memory CD4 T cells inhibits the viral replication in the CD62L(-) cells, with the naive cells capable of completely repressing the virus. Although this inhibition was previously thought to be specific to bead-bound anti-CD3/CD28 stimulation, we show that the same suppression is obtained with sufficiently strong anti-CD3/B7.1 stimulation. Our results show that inhibitory mechanisms, expressed predominantly by strongly stimulated naive CD4 T cells and mediated independently of CCR5-binding chemokines, play a role in the inhibition of R5 HIV replication in CD4 T cells upon CD28 costimulation.
Antigens, CD↗
Models of anergy in the human Jurkat T cell line.
We investigated two model systems to study anergy in a human T cell line. OKT3 or calcium ionophore stimulation of Jurkat cells, in the absence of costimulation, resulted in a steep reduction in the transcription and secretion of IL-2 in response to subsequent stimulation via CD3 and CD28. Treatment of anergic Jurkat cells with the combination of the phorbol ester, PMA, and ionomycin restored IL-2 production in cells rendered anergic by both mechanisms. However, hydrogen peroxide, which also stimulates kinases downstream of the proposed block that occurs in anergic murine cells, did not reverse the anergic state of these cells induced by either stimulus. The cause of unresponsiveness in these two models was found to differ. OKT3-induced anergy resulted in a substantial down-regulation of the CD3 on these cells. In contrast, anergy induced by treatment with a calcium ionophore did not result in CD3 down-regulation. These data indicate that the Jurkat cell line may serve as a suitable model for studying anergy in human T cells; however, the mechanism by which anergy is induced may vary dramatically in response to these two commonly used anergy-inducing strategies. Understanding the similarities and differences between these two models of anergy may lead to a better overall understanding of the anergic state of the T cell.
CD28 Antigens↗
Generation and biochemical analysis of human effector CD4 T cells: alterations in tyrosine phosphorylation and loss of CD3zeta expression.
Human effector T cells have been difficult to isolate and characterize due to their phenotypic and functional similarity to the memory subset. In this study, a biochemical approach was used to analyze human effector CD4 T cells generated in vitro by activation with anti-CD3 and autologous monocytes for 3 to 5 days. The resultant effector cells expressed the appropriate activation/differentiation markers and secreted high levels of interferon gamma (IFN-gamma) when restimulated. Biochemically, effector CD4 T cells exhibited increases in total intracellular tyrosine phosphorylation and effector-associated phosphorylated species. Paradoxically, these alterations in tyrosine phosphorylation were concomitant with greatly reduced expression of CD3zeta and CD3epsilon signaling subunits coincident with a reduction in surface T-cell receptor (TCR) expression. Because loss of CD3zeta has also been detected in T cells isolated ex vivo from individuals with cancer, chronic viral infection, and autoimmune diseases, the requirements and kinetics of CD3zeta down-regulation were examined. The loss of CD3zeta expression persisted throughout the course of effector T-cell differentiation, was reversible on removal from the activating stimulus, and was modulated by activation conditions. These biochemical changes occurred in effector T cells generated from naive or memory CD4 T-cell precursors and distinguished effector from memory T cells. The results suggest that human effector T-cell differentiation is accompanied by alterations in the TCR signal transduction and that loss of CD3zeta expression may be a feature of chronic T-cell activation and effector generation in vivo. (Blood. 2001;97:3851-3859)
CD3 Complex↗
Analysis of amplified T cell receptor V beta transcripts by a non-isotopic immunoassay.
We have recently described a new colorimetric DNA enzyme immunoassay (DEIA) for detecting specific hybrids of complementary nucleic acids. This technology is based on an antibody that selectively recognizes double, but not single stranded DNA and therefore reveals the hybridization event independently from the DNA sequences. Most importantly, the test has an ELISA format and is very rapid and convenient for processing large numbers of samples. In the present report we have adapted this method to reveal the specificity of amplified T cell receptor V beta transcripts. V beta genes were amplified by polymerase chain reaction, using family specific primers and the specificity of the amplified products was determined by Southern blot and by DEIA. Our data demonstrate that DEIA had the same degree of sensitivity and specificity of conventional Southern hybridization. The possibility of analyzing amplified products with the simplicity of a conventional immunoassay should greatly facilitate the analysis of complex multigenic systems such as the T cell receptor and the immunoglobulin repertoire.
Antigens, Differentiation, T-Lymphocyte↗
The neuropeptides VIP and PACAP inhibit IL-2 transcription by decreasing c-Jun and increasing JunB expression in T cells.
Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP) act as macrophage and T-cell deactivators. Previously we established that VIP/PACAP limit T-cell activation directly, by inhibiting interleukin 2 (IL-2), and indirectly, by reducing the macrophage costimulatory functions. The nature of the IL-2 transcriptional factors affected by VIP/PACAP has not been elucidated. Here we investigate the effect of VIP on the AP-l complexes bound to several regulatory sites. VIP/PACAP downregulate c-Jun, and upregulate JunB mRNA and protein. The reduction in c-Jun correlates with the inhibition of the c-Jun N-terminal kinase (JNK). The effects of VIP/PACAP on c-Jun and JunB expression lead to changes in the composition of the AP-l complexes, from c-Jun/Fos to JunB/Fos dimers, with a subsequent decrease in DNA binding and loss of transactivating activity.
Animals↗
Activation or destruction of T cells via macrophages.
Macrophages (MPhi) affect the T cell response in two mutually exclusive ways: activation or deletion. A MPhi type with T cell activating functions (M1) is able to express and upregulate receptors of the B7 family. IFN-gamma favours this MPhi differentiation pathway via upregulation of CD80 (B7-1) and CD86 (B7-2). The treatment of MPhi with IFN-gamma enhances the alphaCD3-mediated T cell blast transformation and reduces the fraction of deleted T cells. This MPhi type may prevent antibody-mediated T cell destruction by the expression of costimulatory receptors. An IL-10-induced MPhi type (M2) fails to express costimulatory molecules of the B7 family but is an effective cell for T cell destruction. Forming cellular conjugates with T cells through antibodies or immune complexes, M2-MPhi preferentially delete targeted cells in vitro and in vivo.
Antibodies, Monoclonal↗
Activated T lymphocytes regulate hyaluronan binding to monocyte CD44 via production of IL-2 and IFN-gamma.
Interactions of the cell surface proteoglycan CD44 with the extracellular matrix glycosaminoglycan hyaluronan (HA) are important during inflammatory immune responses. Our previous studies indicated that monocyte HA binding could be induced by TNF-alpha. Moreover, monocyte HA binding could be markedly up-regulated by culturing PBMC with anti-CD3 (TCR complex) mAbs. The present study was undertaken to identify soluble factors and/or cell surface molecules of activated T lymphocytes that might regulate HA binding to monocytes. Abs to IL-1 alpha, IL-1 beta, IL-2, IL-3, IL-10, IL-15, GM-CSF, IFN-gamma, and TNF-alpha were tested for their effects on anti-CD3 mAb-, Con A-, and PMA/ionomycin-mediated monocyte HA binding in PBMC cultures. Anti-TNF-alpha, anti-IL-2, and anti-IFN-gamma Abs, when added together to PBMC cultures, completely blocked Con A- and partially blocked anti-CD3- and PMA/ionomycin-induced monocyte HA binding. Furthermore, when added together to PBMC cultures, IL-2 and TNF-alpha induced high levels of monocyte HA binding. Likewise, IFN-gamma augmented TNF-alpha-induced monocyte HA binding. To investigate the role of T cell-monocyte direct contact in induction of monocyte HA binding, we studied PMA/ionomycin-activated, paraformaldehyde-fixed CD4(+) T cells in these assays. Fixed, PMA/ionomycin-activated CD4(+) T lymphocytes induced monocyte HA binding, but direct T cell-monocyte contact was not required. Moreover, anti-IFN-gamma and anti-TNF-alpha Abs blocked fixed PMA/ionomycin-activated CD4(+) T cell-induced monocyte HA binding. Taken together, these studies indicate roles for soluble T lymphocyte-derived factor(s), such as IL-2 and IFN-gamma, and a role for monocyte-derived TNF-alpha in Con A-, TCR complex-, and PMA/ionomycin-induced HA binding to monocyte CD44.
Binding Sites↗
Selective impairment of T lymphocyte activation through the T cell receptor/CD3 complex after cytomegalovirus infection.
Cytomegalovirus (CMV) infection is reported to cause transient immunosuppression in man. In this study we have analysed the effect of CMV on T lymphocyte function in 29 children diagnosed for acute CMV infection. Peripheral blood mononuclear cells (PBMC) obtained from the patients showed a significant specific impairment in their proliferative response to enterotoxins A and C1, to concanavalin A and to the anti-CD3 MoAb OKT3. The impaired responses were corrected with exogenous IL-2. In contrast, stimulation using phytohaemagglutinin, as well as activation signals delivered through the surface molecules CD26 or CD28, elicited normal proliferative responses in CMV PBMC. The results indicate that the T cell anergy associated with CMV infection is restricted to the T cell receptor/CD3 activation pathway.
Antigens, CD↗
Obligatory cross-talk with the tyrosine kinases assembled with the TCR/CD3 complex in CD4 signal transduction.
Dissection of the CD4 signal transduction pathway has revealed striking similarities with the TCR/CD3 pathway. Furthermore, downstream signaling by CD4 is impaired in cells lacking surface TCR, suggesting a role for the TCR/CD3 complex in CD4 signal transduction. We have investigated the molecular basis for the dependence of CD4 signaling on TCR/CD3 expression. Using the phosphotyrosine binding domains of the Shc adaptor and the Fyn kinase, which both participate in CD4 signaling, as baits, we show that CD4 induces tyrosine phosphorylation of a subset of the proteins phosphorylated in response to TCR/CD3 engagement. The phosphoprotein patterns were dramatically altered in cells defective for TCR/CD3 expression, and were recoverable by reconstitution of correctly assembled TCR, suggesting that CD4 uses TCR/CD3-associated tyrosine kinases to signal. Among the tyrosine kinases associated with the resting TCR/CD3 complex, only Fyn is activated following CD4 engagement. The failure of Fyn to become phosphorylated in cells defective for TCR expression underlines the unique role of TCR/CD3 associated Fyn in CD4 signal transduction. While no calcium mobilization was measurable in cells defective for TCR/CD3 expression in response to CD4 engagement, the Ras/MAP kinase pathway could be partially activated. Thus, CD4 activates at least two signaling pathways, and tyrosine kinases associated with the TCR/CD3 complex are key components of one of these pathways.
Adaptor Proteins, Signal Transducing↗
MHC class I and class II molecules are expressed in both human and mouse prostate tumor microenvironment.
BACKGROUND: There has been a determined search for therapies specifically aimed at eradicating tumor cells while leaving normal host cells unaffected. This goal can potentially be accomplished by engaging tumor antigen-specific T-cell repertoire to attack the tumor. A pre-requisite for a successful T-cell-mediated attack against tumors or pathogens is that the target tissues express major histocompatibility complex (MHC) molecules. Using newer anti-MHC class I and MHC class II antibody reagents, we re-examined the expression of MHC in both human and mouse prostate tumors and their microenvironments. METHODS: Using immunocytochemistry, we examined the expression of MHC class I, class II, and CD3 molecules on cryopreserved human and mouse prostate tumor samples. RESULTS: MHC class I molecules are expressed by the entire spectrum of different stages of both human and mouse prostate tumor cells. Additionally, cells of the hematopoietic lineage, dispersed in the tumor microenvironment, showed significant expression of MHC class II molecules. Human prostate tumors also show a significant infiltrate of CD3+ T cells. CONCLUSIONS: Expression of MHC class I and class II molecules within the prostate tumor microenvironment are consequential for T-cell-mediated immunotherapeutic approaches against prostate cancer.
Aged↗
Two-step TCR zeta/CD3-CD4 and CD28 signaling in T cells: SH2/SH3 domains, protein-tyrosine and lipid kinases.
A central question in T-cell immunity concerns the nature of intracellular signaling from the antigen receptor, the CD4/CD8 co-receptors and the CD28 antigen. Since the original discovery that T-cell receptors such as CD4 can interact with intracellular protein-tyrosine kinases such as p56lck, remarkable progress has been made in deciphering the signaling pathways that control T-cell growth and immune function. Here, Christopher Rudd and colleagues examine the role of protein-tyrosine kinases, SH2/SH3 domains and lipid kinases in the generation of signals from the TCR zeta/CD3 complex and the CD28 antigen.
Amino Acid Sequence↗
Prion protein is a component of the multimolecular signaling complex involved in T cell activation.
In this study we analyzed the interaction of prion protein PrP(C) with components of glycosphingolipid-enriched microdomains in lymphoblastoid T cells. PrP(C) was distributed in small clusters on the plasma membrane, as revealed by immunoelectron microscopy. PrP(C) is present in microdomains, since it coimmunoprecipitates with GM3 and the raft marker GM1. A strict association between PrP(C) and Fyn was revealed by scanning confocal microscopy and coimmunoprecipitation experiments. The phosphorylation protein ZAP-70 was immunoprecipitated by anti-PrP after T cell activation. These results demonstrate that PrP(C) interacts with ZAP-70, suggesting that PrP(C) is a component of the multimolecular signaling complex within microdomains involved in T cell activation.
Adaptor Proteins, Signal Transducing↗
Therapeutic potential of a tumor-specific, MHC-unrestricted T-cell receptor expressed on effector cells of the innate and the adaptive immune system through bone marrow transduction and immune reconstitution.
T-cell receptor (TCR) with unique major histocompatibility complex (MHC)-unrestricted antigen-binding properties was isolated from a human T-cell clone specific for the tumor antigen MUC1. This TCR binds its epitope on the MUC1 protein without the requirement of processing and presentation. A single-chain Valpha/Vbeta/Cbeta (scTCR) was fused to a CD3 zeta (zeta) chain to allow expression on the surface of cells of the innate (granulocytes, macrophages, natural killer [NK] cells) as well as the adaptive (T and B cells) immune system. To test the ability of the cells of the innate immune system to reject a tumor when provided with a tumor antigen-specific TCR, we reconstituted severe combined immunodeficiency (SCID) mice with bone marrow cells transduced with a retroviral vector encoding this receptor and challenged them with a MUC1-positive human tumor. These mice controlled the growth of the tumor significantly better than the control mice. We performed a similar experiment in immunocompetent mice transgenic for human MUC1. Expression of the TCR on large percentages of cells did not result in infiltration or destruction of tissues expressing MUC1. Reconstituted mice controlled the outgrowth of a MUC1-transfected but not the parental control tumor. scTCR expression appears lifelong, suggesting a successful transduction of the self-renewing stem cells.
Amino Acid Sequence↗
Resetting the functional capacity of regulatory T cells: a novel immunotherapeutic strategy to promote immune tolerance.
Over the last few years, there has been a re-emergence of the concept of suppressor/regulatory T cells among the central players of immune mechanisms controlling a wide variety of immune responses from physiological autoreactivity (i.e., response to self-antigens) to responses to transplants, tumours and infectious antigens. Regulatory T cells are diverse in their phenotypes, antigen specificity, mode of action and immunopathological relevance. This review briefly summarises studies from the authors' group showing that specialised subsets of regulatory T cells are instrumental in the control of autoimmune diseases and more specifically of Type 1 diabetes. In addition, this review will provide evidence supporting the notion that CD3-specific monoclonal antibodies are representatives of a new category of immunotherapeutic agents that possess the unique capacity to promote immunological tolerance (an antigen-specific unresponsiveness in the absence of long-term generalised immunosuppression) through their ability to induce immunoregulatory T cells.
Animals↗
Modulation of CD28 expression: distinct regulatory pathways during activation and replicative senescence.
The costimulatory molecule CD28 has a restricted tissue distribution and is expressed on T cells and some plasmacytoma cells. Although CD28 is constitutively expressed, its expression is transiently down-regulated following T cell activation and declines progressively with in vitro senescence. In vivo, CD8+ T cells and, less frequently, CD4+ T cells may completely lose CD28 surface expression during chronic infections and with aging. This correlates with changes of nuclear protein-binding activities to two motifs, site alpha and beta, within the CD28 minimal promoter. Both alpha- and beta-bound complexes are found only in lymphoid tissues, in CD28+ T cells, and in some transformed B cells. These complexes are coordinately expressed except during replicative senescence, which is characterized by the down-modulation of site beta- but not site alpha-binding activities. In contrast, T cell activation induces a parallel decline in both site alpha- and beta-binding activities. CD4+ and CD8+ T cells differ in their beta-binding profiles, which may explain the more pronounced down-regulation of CD28 in senescent CD8+ T cells. In vivo expanded CD4+CD28null and CD8+CD28null T cells uniformly lack alpha- and beta-bound complexes, resembling the pattern seen in chronically activated cells and not of senescent cells.
Antibodies, Monoclonal↗
Anti-CD3 monoclonal antibody treatment of patients with CD3-negative tumors: a phase IA/B study.
Anti-CD3 monoclonal antibodies induce the proliferation of human T-cells in vitro and activate specific and nonspecific cytolysis by human T-cell clones and human peripheral blood lymphocytes. In vivo administration of anti-CD3 prevents tumor growth of a UV-induced mouse fibrosarcoma. We conducted a phase I trial to determine the toxicity and immunomodulatory properties of low doses of anti-CD3 in 36 patients with cancer. In 23 patients, anti-CD3 was given i.v. over 3 h at 1, 10, 30, and 100 mcg/patient. Five other patients received anti-CD3 at 30 mcg by i.v. bolus. Patients were treated every 3 days for a total of four doses. An additional eight patients received anti-CD3 daily for 14 days at 3 mcg by i.v. bolus, 3-h infusion, or 24-h infusion. Dose-limiting toxicity was headache. Headache was often accompanied by signs and symptoms of meningeal irritation leading to performance of a lumbar puncture in nine patients. The opening pressure was usually elevated, and six patients had a cerebrospinal fluid lymphocytosis with an elevated protein. Increased levels of interleukin 6 were identified in the cerebrospinal fluid. The maximum tolerated dose by 3-h infusion was 30 mcg. There were no objective tumor responses. There was a dose-related increase in the number of peripheral blood lymphocytes expressing the T-cell activation antigen CD69 (Leu 23), but no changes were seen in CD25 (interleukin 2 receptor) expression, and no changes were observed in the serum levels of the soluble interleukin 2 receptor. Even at these low doses of anti-CD3, 8 of 16 patients tested developed human anti-mouse antibodies.
Adult↗
[Expression of zeta (zeta) chain in peripheral blood T lymphocytes and NK cells of children with idiopathic nephrotic syndrome (INS)--preliminary results].
UNLABELLED: Cellular immune disturbances have been implicated in the pathogenesis of idiopathic nephrotic syndrome. The zeta (zeta) chain, which is a component of the TCR/CD3 complex and CD16 heterodimer in NK cells, plays a crucial role in signal transducing events leading to T and NK cell activation and proliferation. The aim of our study was to examine the zeta (zeta) chain expression in peripheral blood CD4+, CD8+ T-lymphocytes and NK cells (CD3-/CD56+) derived from children with NS in active phase of the disease and in remission. We also examined the effect of 24 and 72 h anti-CD3+rIL-2 stimulation on the zeta chain expression in all studied groups. MATERIAL AND METHODS: The study group consisted of 8 children with INS in active phase of the disease, 11 children with INS in clinical remission and 15 age-matched healthy controls. The level of zeta (zeta) chain expression, assessed by flow cytometry, was determined as the mean fluorescence intensity (MFI). RESULTS: In INS patients with active phase MFI values for CD4+ cells were higher than in children with remission and in controls. The levels of zeta in CD4+ T-lymphocytes of patients with remission were comparable to those in controls. There were no differences between zeta levels on NK cells in examined groups. Ex vivo stimulation had no impact on zeta expression in children with acute phase of NS, whereas in patients on remission stimulation with anti-CD3+rIL-2 increased zeta expression on CD4+ cells and decreased it on NK cells. NK zeta expression was also diminished in the control group. CONCLUSIONS: Preliminary results point at the alterations of zeta expression in children with INS as a probable cause of immune dysregulation in this group of patients.
Adolescent↗