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At least 1,153 records · Page 64Linked to original sources
PubMed1993

CD28 ligation by monoclonal antibodies or B7/BB1 provides an accessory signal for the cyclosporin A-resistant generation of cytotoxic T cell activity.

Ligation of the T cell membrane Ag CD28 with mAb 9.3 or with its natural ligand B7/BB1 on accessory cells has been shown to provide a helper signal for stimulation through the TCR/CD3 complex. The present study was undertaken to investigate whether CD28 could function as an accessory signal receptor in the generation and effector phase of CTL activity. Purified resting human T cells were activated for 3 to 4 days with immobilized anti-CD3 mAb as the primary stimulus, and CTL activity was then measured by an anti-CD3-redirected 4-hr 51Cr release assay on Fc gamma R-bearing P815 target cells. When the concentration of immobilized anti-CD3 mAb as the primary signal for CTL generation was below threshold, CTL activity could be generated by addition of mAb 9.3 to the cultures. At optimal concentrations of immobilized anti-CD3, the addition of anti-CD28 did not further enhance the generation of CTL activity, but under these conditions generation of CTL activity was almost completely resistant to cyclosporin A (CsA) as a result of CsA-resistant IL-2 production. When 3T6 mouse fibroblasts, transfected with Fc gamma RII and B7, were used as accessory cells, anti-CD3 and B7 were also found to generate cytotoxic activity. Cytotoxic T cell generation under these conditions could be blocked by anti-B7 mAb, but was totally resistant to CsA. CTL activity could be generated by CD3 and CD28 ligation in both CD4(+) and CD8(+) subpopulations. Finally, we found that the activity of CTL lines (isolated from ascitic fluid of a patient with ovarian carcinoma and cultured in IL-2) was higher on B7-transfected targets than on the B7(-) targets. We conclude that CD28 ligation provides a major accessory signal for the CsA-resistant generation of CTL activity and that CD28-B7 interaction also enhances cytotoxic effector functions of CTL. These findings might have important implications for immunotherapeutic interventions.

Abatacept↗
PubMed1993

Anti-CD3 and -CD4 monoclonal antibody in the treatment of steroid-resistant renal allograft rejection.

Between November 1987 and October 1991, 40 consecutive cadaveric renal recipients immunosuppressed with cyclosporine (CsA) who developed renal allograft rejection were treated with domestically prepared muromonab CD3 (Wu 338) and CD4 (Wu167). CD3 and CD4 monoclonal antibodies (McAb) as rescue treatment (n = 34) successfully reversed 29 cases of (85.3%) intractable renal allograft rejection (steroid resistant rejection 32 and anti-human thymocyte globulin [AHTG] resistant rejection 2) and completely reversed 4 cases of acute renal rejection episodes CD3 McAb as first-line treatment (n = 4). Two cases of chronic rejection failed in the treatment of McAb. Rejection episodes were reversed from 4 to 11 days (mean 6 days). Combined use of CD3 and CD4 McAb seemed to yield better results. Peripheral blood T lymphocyte subsets showed that CD3+, CD4+ and CD8+ decreased significantly after the treatment of McAb. No severe side-effects were observed in the treatment of McAb. The McAb could be administered safely. Pulmonary infection rate was 15%. The yearly graft survival rate was increased significantly (87.8% vs 80.0%).

Adult↗
PubMed1994

T lymphocytes from alcoholic cirrhotic patients show normal interleukin-2 production but a defective proliferative response to polyclonal mitogens.

T lymphocyte proliferation is a complex process involving intra- and extracellular molecules. T cell activation was studied in T lymphocytes from patients with alcoholic cirrhosis. A defective phytohemagglutinin (PHA)-induced T cell mitogenesis was observed in 60% of these patients. Likewise, their blastogenic response to anti-CD3 was also depressed (p < 0.05). However, the DNA synthesis induced by stimulation with phorbol esters (12-O-tetradecanoil-phorbol-13-acetate) + ionomycin was normal (p > 0.05). These alterations cannot be ascribed either to decreased interleukin-2 synthesis or to a defective interleukin-2 receptor expression after cellular activation. Moreover, supplementation of the PHA-stimulated T cell cultures with saturant concentrations of recombinant interleukin-2 did not normalize the hypoproliferative response of T cells from alcoholic++ cirrhotic patients. These results provide evidence that a generalized alteration in the interactions between either mitogens or interleukin-2 and their receptors can explain the T lymphocyte-defective blastogenesis found in patients with alcoholic cirrhosis.

Antibodies↗
PubMed1996

Alpha 4 beta 1 (CD49d/CD29) integrin costimulation of human T cells enhances transcription factor and cytokine induction in the absence of altered sensitivity to anti-CD3 stimulation.

The integrin alpha 4 beta 1 can provide a costimulus to induce IL-2 secretion and IL-2R expression leading to enhanced proliferation of purified, peripheral blood T cells. Similar to expression of IL-2, we demonstrated that recombinant vascular-cell adhesion molecule-1, when co-immobilized with anti-CD3 mAb, significantly enhanced the induction of transcription factors NF-AT, AP-1, and NF-kappa B as determined by electromobility shift assays. alpha 4 beta 1 ligation alone had no effect on transcription factor binding. The requirements for induction of transcription factors reflected the requirements for the secretion of multiple cytokines, including IL-2, TNF-alpha, IFN-gamma, and granulocyte macrophage-CSF. In contrast to freshly isolated T cells, in vitro-cultured T cells did not require costimulation for cytokine secretion in response to anti-CD3 alone. Comparison of the dose response to anti-CD3 stimulation demonstrated that half-maximal induction of IL-2 was achieved using the same dose of anti-CD3 for both freshly isolated and cultured T cells. Furthermore, the dose of OKT3 required to achieve half-maximal activation was the same using PMA or different concentrations of alpha 4 beta 1 ligands. Therefore, costimulation by alpha 4 beta 1 ligands was not due to stabilization of the interaction of the cells with its substrate. We conclude, rather, that alpha 4 beta 1 in freshly isolated T cells delivers a distinct signal that synergizes early with signals initiated by TCR/CD3 ligation to induce DNA binding of multiple transcription factors required for cytokine gene induction.

CD3 Complex↗
PubMed2025

Proximity between LAG-3 and the T cell receptor guides suppression of T cell activation and autoimmunity.

Therapeutically targeting pathogenic T cells in autoimmune diseases has been challenging. Although LAG-3, an inhibitory checkpoint receptor specifically expressed on activated T cells, is known to bind to major histocompatibility complex class II (MHC class II), we demonstrate that MHC class II interaction alone is insufficient for optimal LAG-3 function. Instead, LAG-3's spatial proximity to T cell receptor (TCR) but not CD4 co-receptor, facilitated by cognate peptide-MHC class II, is crucial in mediating CD4+ T cell suppression. Mechanistically, LAG-3 forms condensate with TCR signaling component CD3&#x3b5; through its intracellular FSAL motif, disrupting CD3&#x3b5;/lymphocyte-specific protein kinase (Lck) association. To exploit LAG-3's proximity to TCR and maximize LAG-3-dependent T cell suppression, we develop an Fc-attenuated LAG-3/TCR inhibitory bispecific antibody to bypass the requirement of cognate peptide-MHC class II. This approach allows for potent suppression of both CD4+ and CD8+ T cells and effectively alleviates autoimmune symptoms in mouse models. Our findings reveal an intricate and conditional checkpoint modulatory mechanism and highlight targeting of LAG-3/TCR cis-proximity for T cell-driven autoimmune diseases lacking effective and well-tolerated immunotherapies.

Animals↗
PubMed2000

Synergistic activation of NF-kappa B by functional cooperation between vav and PKCtheta in T lymphocytes.

Here we identified PKCtheta as an activator of transcription factor NF-kappaB in T cells. PKCtheta-induced NF-kappaB activation was synergistically augmented by Vav. Several experimental approaches revealed that PKCtheta is located downstream from Vav in the control of the pathway leading to synergistic NF-kappaB activation. In addition to the synergistic activation cascade, Vav also triggered NF-kappaB activity on a separate route. CD3/CD28-induced activation of NF-kappaB was inhibited by dominant negative forms of Vav or PKCtheta, revealing their essential role in this activation pathway. The Vav/PKCtheta-mediated signals preferentially activated IkappaB kinase beta. Vav and PKCtheta were found to be constitutively associated in unstimulated T cells. Only the ligation of the costimulatory CD28 receptor, but not of the T cell receptor, resulted in the transient dissociation of the Vav-PKCtheta complex. In contrast, T cell receptor/CD28 costimulation resulted in faster dissociation and slower reassociation kinetics.

Antigens, CD↗
PubMed1993

T cell response to embryonal carcinoma F9 cells: induction and characterization of T cell receptor alpha beta+ double-negative cytotoxic T lymphocytes.

We investigated the mechanism of T cell response to murine embryonal carcinoma F9 cells. Thy-1+, CD4-, CD8- (double-negative) cytotoxic effector cells were induced in spleen cells obtained from immune A.BY mice to F9 cells, and the cytotoxic activity was major histocompatibility complex (MHC)-unrestricted. Furthermore, CD4+ T cells were essential for the induction of double-negative cytotoxic T lymphocytes directed to F9 cells. Most of the double-negative cytotoxic T lymphocyte lines obtained by long-term culture of the effector cells had CD3 molecule and T-cell receptor beta chain on their cell surface, and the CD3 molecule was found to be involved in target cell recognition. The T cell receptor alpha beta+ double-negative cytotoxic T lymphocyte line (2A5) also lysed various tumor cells in a non-MHC-restricted manner, but did not lyse concanavalin A-stimulated blasts of 129 strain, from which F9 cells had originated. These results indicate that T cell receptor alpha beta+ double-negative cytotoxic T lymphocytes induced by F9 cells recognize a common antigen(s) expressed on F9 cells and other tumor cells but not minor histocompatibility antigens.

Animals↗
PubMed2003

TCR subunit specificity of CTLA-4-mediated signaling.

Cytotoxic T-lymphocyte-associated antigen (CTLA)-4 is an activation-induced receptor that down-regulates T cell responses by antagonizing B7-dependent costimulation and/or by transducing a negative signal. The mechanism of CTLA-4-mediated negative signaling is unknown. Recently, it has been postulated that CTLA-4 inhibits T cell activation by causing specific dephosphorylation of the T cell receptor (TCR)-zeta chain of the antigen-receptor complex through an lck-dependent recruitment of the Src homology-2-containing tyrosine phosphatase-2. To test this hypothesis, we generated stably transfected T cell clones expressing doxycycline-inducible CTLA-4 with CD25:TCR-zeta (CD25-zeta) or CD25:CD3-epsilon (CD25-epsilon) fusion proteins. In these clones, ligation of CD25-zeta or of CD25-epsilon with antibodies against CD25 induced full T cell activation, as illustrated by extracellular signal-regulated kinase (ERK) activation and interleukin (IL)-2 production. More importantly, coligation of CTLA-4 with CD25-zeta or of CTLA-4 with CD25-epsilon in the respectively transfected clones inhibited ERK activation and IL-2 production, demonstrating that CTLA-4 does not specifically inhibit signals from TCR-zeta but can also inhibit signals from CD3-epsilon. Our results suggest that the target specificity of CTLA-4 is determined by its coligation with any given transmembrane receptor rather than by its intracellular mediators.

Antigens, CD↗
PubMed2000

TNF-alpha is the critical mediator of the cyclic AMP-induced apoptosis of CD8+4+ double-positive thymocytes.

Apoptosis is one of the key regulatory mechanisms in tissue modeling and development. In the thymus, 95-98% of all thymocytes die by apoptosis because they failed to express a TCR with an optimal affinity for the selecting intrathymic peptide-MHC complexes. We studied the possible role of two prominent nerve growth factor (NGF-TNF) family member systems, Fas ligand (FasL)-Fas receptor (FasR) and TNF-alpha-TNFR, in apoptosis of murine CD8+4+ double-positive (DP) thymocytes induced via TCR-CD3- and cAMP-mediated signaling. TCR-CD3epsilon-mediated apoptosis of DP thymocytes was found not to be dependent on either of the two systems. The FasL-FasR system was also found to be dispensable for the cAMP-mediated apoptosis. By contrast, cAMP agonists (dibutyryl-cAMP and forskolin) induced apoptosis via TNF-alpha, as evidenced by 1) the ability of anti-TNF-alpha mAbs to abrogate cAMP analogue-induced DP apoptosis in a dose-dependent manner; and 2) increased resistance of DP thymocytes from TNF-alpha-/- and TNFR I-/-II-/- animals to cAMP agonist-mediated apoptosis. cAMP agonists induced DP thymocyte death by a combination of two mechanisms: first, they induced selective up-regulation of TNF-alpha production, and, second, they sensitized DP thymocytes to TNF-alpha. The latter effect may be due to the down-regulation of TNFR-associated factor 2 protein. These results identify TNF-alpha as the critical mediator of cAMP-induced apoptosis in thymocytes and provide a molecular explanation for how the cAMP stimulators, including the sex steroids, may modulate T cell production output, as observed under physiological and pharmacological conditions.

Animals↗
PubMed2001

Crosslinking CD81 results in activation of TCRgammadelta T cells.

CD81 is expressed on most cells and is associated with other glycoproteins, including CD4 and CD8, to form multimolecular membrane complexes. Crosslinking of CD81 on TCRalphabeta(+) T cells results in costimulatory signals that have been proposed to be mediated via CD4 or CD8. In this study, we show that CD81 is also expressed on TCRgammadelta(+)CD4(-)CD8(-) T cells. CD81 crosslinking greatly enhanced anti-CD3 activation of both TCRalphabeta(+) (CD4+ and CD8+) and TCRgammadelta(+) T cells with regard to IFN-gamma production. However, crosslinking of CD81 molecules on TCRgammadelta(+) T cells, in the absence of anti-CD3 stimulation, resulted in cytokine production and enhanced IL-2-induced proliferation, demonstrating that physical association with CD4 or CD8 is not necessary for CD81 signaling. In contrast, crosslinking of CD81 on TCRalphabeta(+) T cells, in the absence of anti-CD3 stimulation, failed to activate these T cells. These results suggest that CD81 signaling may be mediated via a different mechanism(s) in TCRgammadelta(+) versus TCRalphabeta(+) T cells.

Antigens, CD↗
PubMed1987

The 2H4 molecule but not the T3-receptor complex is involved in suppressor inducer signals in the AMLR system.

It is suggested that autologous mixed lymphocyte reaction (AMLR) may play an important role in generating suppressor inducer signals and in down-regulating the immune response following self-major histocompatibility recognition. In the present study, monoclonal antibodies directed at cell surface structures on T4+ cells activated in AMLR were used to define the molecules important in the generation of the suppressor inducer signal. The density of a 200/220-kDa structure, termed 2H4, increased on T4 cells during activation in AMLR and furthermore a strong correlation was observed between the generated suppressor inducer activity of such cells and the density of the 2H4 antigen. More importantly, we showed that treatment of AMLR activated T4 cells with anti-2H4 but not anti-T3 or T4 antibody abolished the suppressor inducer function of these cells. These results suggest that the 2H4 molecule but not the T3-receptor complex plays an important role in generating suppressor inducer signals in the AMLR system.

Antibodies, Monoclonal↗
PubMed2003

High-resolution multicolor imaging of dynamic signaling complexes in T cells stimulated by planar substrates.

The dynamic visualization of developing immunological synapses has been hindered by the difficulty of imaging the contact between the T cell and the antigen-presenting cell (APC). Here, we describe a technique in which T cell responses are constrained to a planar stimulatory substrate. This approach, when used in conjunction with immunofluorescent staining procedures or fluorescent protein tags, greatly facilitates detection of the dynamic molecular rearrangements that accompany the formation of contacts and the initiation of signal transduction through the T cell receptor (TCR). Using this method, we have observed signaling complexes of dynamically varying compositions that possess distinct fates.

Animals↗
PubMed1998

Effects of age and gonadal steroids on the localization of antigen-presenting cells, and T and B cells in the chicken oviduct.

The effects of age and gonadal steroids on the localization of immunocompetent cells, including antigen-presenting cells that contain the major histocompatibility complex (MHC) class II antigen, and T and B cells in the chicken oviduct were studied. Oviductal tissues were collected from laying and immature hens treated with diethylstilboestrol (an analogue of oestrogen) or progesterone. Cryostat sections of the tissues were immunostained for MHC class II, CD3 (T-cell antigen) and Bu-1 (immature B-cell antigen), and examined under a light microscope and an image analysis system. MHC class II+, CD3+ and Bu-1+ cells were observed in the mucosal epithelium and stromal connective tissue of both the laying and immature hens. MHC class II+ cells in the oviductal stroma appeared in association with oviductal development during sexual maturation and increased with ageing thereafter. The infiltration of CD3+ and Bu-1+ cells into the oviductal tissues increased in young laying hens compared with immature hens and decreased in old laying hens compared with young laying hens. Diethylstilboestrol increased the population of MHC class II+ and CD3+ cells in the stroma of the infundibulum and vagina, but had no significant effect on the population of Bu-1+ cells in the oviduct of immature hens. Progesterone increased the population of CD3+ cells in the stromal tissue of oviductal segments from all hens, and of Bu-1+ cells in the mucosal epithelium of the infundibulum and magnum, but had little effect on the frequency of MHC class II+ cells in the oviduct of immature hens. There were typically more immunocompetent cells in the infundibulum and vagina than in the other oviductal segments in laying hens and immature hens treated with sex steroids. These results suggest that local immunity in the chicken oviduct is enhanced during sexual maturation and possibly decreases during ageing. Gonadal steroids may play a significant role in the regulation of local immunity in the oviduct. The effects of oestrogen and progesterone on the influx of these immunocompetent cells into the oviduct differs among cell types and oviductal segments.

Aging↗
PubMed1991

Signal transduction through the T cell antigen receptor. Activation of phospholipase C through a G protein-independent coupling mechanism.

The T cell Ag (Ti-CD3) receptor complex has been proposed to regulate phosphoinositide-specific phospholipase C (PLC) through a cholera toxin (CTX)-sensitive guanine nucleotide-binding (G) protein. In this study, we have used CTX and staurosporine as pharmacologic probes to further define the linkage between the Ti-CD3 receptor and PLC activity in the human T cell line, Jurkat. CTX pretreatment inhibited Ti-CD3 receptor-dependent phosphoinositide hydrolysis and, concomitantly, protein tyrosine kinase activation in intact cells. Studies with electrically permeabilized Jurkat cells revealed that guanosine 5'-(3-O-thio) triphosphate stimulated an increase in PLC activity, that unlike the response to Ti-CD3 receptor ligation, was not affected by cellular pretreatment with CTX. In contrast, the phosphotyrosine phosphatase inhibitors, orthovanadate and molybdate anions, stimulated phosphoinositide hydrolysis in permeabilized cells through a CTX-sensitive mechanism of PLC activation. Additional studies with a known PTK inhibitor, staurosporine, supported the results obtained with CTX. Staurosporine pretreatment inhibited the phosphoinositide hydrolysis induced by anti-CD3 antibodies or phosphotyrosine phosphatase inhibitors, but failed to alter the G protein-dependent PLC activation response to guanosine 5'-(3-O-thio) triphosphate. The results of this study indicate that PLC activity(s) in Jurkat cells are regulated by both G protein- and PTK-dependent coupling mechanisms. However, the differential inhibitory effects of CTX and staurosporine on these PLC activation pathways strongly suggest that a protein tyrosine kinase activation event, rather than a G protein, mediates the functional linkage between the Ti-CD3 receptor and PLC activity in Jurkat cells.

Alkaloids↗
PubMed1988

Lysis of cells infected with HIV-1 by human lymphocytes targeted with monoclonal antibody heteroconjugates.

The present study was undertaken to determine whether human PBL can be specifically focused to lyse cells infected with HIV-1 by mAb heteroconjugates that can bridge target and effector cells. A mAb directed against the central portion of HIV-1 glycoprotein gp110 was chemically cross-linked to a mAb directed against the CD3/TCR complex or to a mAb directed against the CD16 Fc gamma-R expressed on large granular lymphocytes (LGL). HIV-1-infected cells, but not uninfected cells, were found to be lysed to a greater extent by PBL in the presence of the gp110 X CD3 or the gp110 X CD16 antibody heteroconjugate than in the presence of the single antibodies or a mixture of the mAb comprising the heteroconjugates. Pretreatment of PBL with anti-CD3 or IL-2 augments their ability to lyse HIV-1-infected cells in the presence of the heteroconjugates. Lysis by anti-CD3-activated PBL in the presence of the gp110 X CD3 heteroconjugate was found to be mediated by CD8+-enriched T cells, whereas lysis by IL-2-treated PBL in the presence of the gp110 X CD16 heteroconjugate is mediated by PBL enriched for CD16+ cells, which are primarily LGL. Furthermore, PBL from asymptomatic, HIV-1-infected seropositive donors were found to be functional in lysing HIV-1-infected cells in the presence of the antibody heteroconjugates. Such antibody heteroconjugates, which can target T cells or LGL to lyse HIV-1-infected cells, may be of prophylactic or therapeutic value in HIV-1-infected individuals.

Antibodies, Monoclonal↗
PubMed1988

The T-cell antigen receptor: a complex signal-transducing molecule.

The T cell antigen-specific receptor (TCR) on most mature T cells is a multisubunit complex composed of 7 chains: alpha, beta, gamma, delta, epsilon, and either a zeta-zeta homodimer (zeta 2) or a zeta-eta heterodimer (zeta eta). We have derived a series of TCR variants and mutants from the antigen-specific murine T cell hybridoma, 2B4.11, permitting detailed analyses of the assembly and transport of the TCR. Loss of the zeta chain resulted in markedly reduced cell surface TCR expression. This was due to enhanced degradation of the other TCR chains in a post-Golgi, probably lysosomal, compartment. Loss of the beta chain, delta chain, or the combination of delta and zeta chains, also resulted in loss of cell surface TCR expression. Unlike the zeta loss variants, in these cases the other TCR chains were retained in the ER. Epsilon, gamma, and zeta could survive for prolonged periods in the ER, while the alpha, beta, and delta chains were rapidly and efficiently degraded. In another series of studies, variants that were deficient in the eta chain but that expressed normal levels of zeta 2-containing TCRs were analyzed for their functional properties. A positive relationship was found between the presence of zeta eta and the ability to respond to mitogenic stimuli with increases in phosphoinositide hydrolysis and, in one well characterized variant, increases in intracellular Ca2+. Despite this, late biological responses such as interleukin 2 (IL-2) production and inhibition of transformed growth were relatively normal. These results call into question the putative cause-and-effect relationship between some early biochemical events and these late biological responses. Further, they suggest a model in which zeta eta-containing TCR complexes are largely responsible for activation-induced phosphoinositide hydrolysis.

Animals↗
PubMed1997

Hematopoietic changes induced by a single injection of anti-CD3 monoclonal antibody into normal mice.

The present study evaluates hematopoietic modifications consecutive to in vivo treatment of mice with anti-CD3 monoclonal antibodies (mAb). The hamster mAb 145-2C11, administered in a single i.v. injection of 10 micrograms, induced the release of both interleukin 3 (IL-3) and GM-CSF into the circulation. IL-3 could be detected in the serum within 1 h, attained maximal levels after 4 h and had disappeared after 24 h. Three days later, treated mice exhibited a two- to threefold rise in blood neutrophil levels and increased spleen cell counts. Concomitantly, the incidence of nucleated erythroid cells in these spleens increased around 10-fold, relative to controls having received hamster Ig. At the same time point, clonogenic progenitor frequencies were 10-fold higher in spleens from treated mice than in those from control mice. Furthermore, the responsiveness of these splenocytes to IL-3, in terms of histamine synthesis, was enhanced. In contrast, bone marrow cell populations were only slightly affected by anti-CD3 injection. All hematopoietic changes required multivalent crosslinking of the mAb for induction, since F(ab')2 fragments lacked this activity. A return to normal occurred 7-10 days after treatment. Two i.v. injections of recombinant murine IL-3 together with recombinant murine GM-CSF on a single day had a less pronounced effect on progenitor cell frequencies in the spleen than treatment with anti-CD3. This difference is probably due to the amplification of growth factor-induced hematopoiesis by the interaction with other cytokines generated in response to anti-CD3.

Animals↗