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PubMed2001

Central role of leukemia-derived factors in the development of leukemia-associated immune dysfunction.

INTRODUCTION: The underlying mechanism of tumor-associated T-cell dysfunction has been suggested to be due to an acquired abnormality in the T-cell receptor signaling complex, however, tumor-derived inhibitory factors acting on immune effectors could also explain the observed immunosuppression. Here, in a murine acute leukemia model, responses (proliferation and IL-2 secretion) to mitogens were suppressed in the early stages of leukemic progression due to a leukemia-derived soluble factor(s). MATERIALS AND METHODS: Correlations between the development of immunosuppression and changes in expression of TCR signaling proteins (CD3-zeta, p56(lck), p59(fyn)), calcium mobilization, and total tyrosine kinase activity following TCR stimulation were examined. RESULTS: In contrast to reduced responses to mitogens seen as early as 1 week following injection of leukemic cells, signaling abnormalities were only seen in advanced disease (ie four weeks). The only significant alteration in signaling protein expression was loss of CD3-zeta for four weeks following the initiation of leukemia. Importantly, a direct role of a leukemia-derived soluble factor(s) in the loss of CD3-zeta could be shown in vitro by co-culturing splenocytes with leukemic cells separated by a transwell for seven to 10 days. Further studies demonstrated that the leukemia-derived factor(s) stimulated splenic macrophages to secrete a second soluble factor(s) that caused the loss of CD3-zeta. CONCLUSION: These data indicate that soluble leukemia-derived factor(s) have both immediate immunosuppressive actions and a later effect acting indirectly to induce intrinsic defects in T-cell signaling pathways via accessory cells. In some tumors, there is evidence that the soluble factor is Fas-ligand, which induces apoptosis in tumor-infiltrating T cells and the action of activated caspases cleave CD3-zeta. In this model, the soluble factor prevents apoptosis indicating a second mechanism is responsible for the loss of T-cell signaling proteins.

Acute Disease↗

PubMed2006

NOD.c3c4 congenic mice develop autoimmune biliary disease that serologically and pathogenetically models human primary biliary cirrhosis.

Primary biliary cirrhosis (PBC) is an autoimmune disease with a strong genetic component characterized by biliary ductular inflammation with eventual liver cirrhosis. The serologic hallmark of PBC is antimitochondrial antibodies that react with the pyruvate dehydrogenase complex, targeting the inner lipoyl domain of the E2 subunit (anti-PDC-E2). Herein we demonstrate that NOD.c3c4 mice congenically derived from the nonobese diabetic strain develop an autoimmune biliary disease (ABD) that models human PBC. NOD.c3c4 (at 9-10 wk, before significant biliary pathology) develop antibodies to PDC-E2 that are specific for the inner lipoyl domain. Affected areas of biliary epithelium are infiltrated with CD3+, CD4+, and CD8+ T cells, and treatment of NOD.c3c4 mice with monoclonal antibody to CD3 protects from ABD. Furthermore, NOD.c3c4-scid mice develop disease after adoptive transfer of splenocytes or CD4+ T cells, demonstrating a central role for T cells in pathogenesis. Histological analysis reveals destructive cholangitis, granuloma formation, and eosinophilic infiltration as seen in PBC, although, unlike PBC, the extrahepatic biliary ducts are also affected. Using a congenic mapping approach, we define the first ABD (Abd) locus, Abd1. These results identify the NOD.c3c4 mouse as the first spontaneous mouse model of PBC.

Adoptive Transfer↗

PubMed1992

Enhancing effect of pokeweed mitogen on the proliferation and the cytotoxicity of lymphokine-activated killer cells.

In order to obtain more potent lymphokine-activated killer (LAK) cells for use in adoptive immunotherapy, pokeweed mitogen (PWM) was added to the culture medium for the initial 24-48 h of culturing. The proliferation rate of PWM-stimulated LAK cells reached about 1000-fold after 3-week culture. This rate was nearly the same as that of LAK cells stimulated by 10 ng/ml of OKT3, the mouse anti-CD3 monoclonal antibody. However, the cytotoxicity of PWM-stimulated LAK cells was significantly more potent than that of OKT3-stimulated LAK cells. Phenotypic analysis revealed that PWM-stimulated LAK cells were CD3+CD56(+)-dominant while OKT3-stimulated LAK cells were CD3+CD56(-)-dominant. About half of CD3+CD56+ PWM-stimulated LAK cells was CD8+. These results suggest that more efficient adoptive immunotherapy is possible by using high-dose PWM-stimulated LAK cells with more potent cytotoxicity. Interleukin-1 beta and tumor necrosis factor alpha were significantly increased in the culture media after 24-h incubation with 1 micrograms/ml of PWM. Secretion of interferon-gamma was not enhanced by this concentration of PWM within 24 h. Therefore, PWM is considered to activate monocytes or macrophages to produce these cytokines in advance, influencing the proliferation and the cytotoxicity of LAK cells.

Antigens, CD↗

PubMed2005

Reduced primary T lymphopoiesis in 3-month-old lurcher mice: sign of premature ageing of thymus?

OBJECTIVE: The nervous, endocrine and immune systems are functionally interconnected so that they may form a complex metasystem. Abnormalities within the neuroendocrine compartment can thus affect immune mechanisms and vice versa. The Lurcher-type mutation in mice has a profound impact on brain development in both homozygous and heterozygous individuals, which is followed by immune system changes. We investigated whether macroscopic changes in the thymus size were associated with an altered thymocyte development or with changes in peripheral T cell subset distribution. METHODS: CD3, CD4 and CD8 expressions on thymocytes and peripheral T cells were compared with those in wild-type and Lurcher heterozygous C3H mice using surface immunophenotyping and flow cytometry. Galanthus nivalis agglutinin binding to thymocytes was measured at the same time. RESULTS: While no differences between experimental groups were observed in 1-month-old mice, a critical reduction of numbers of thymocytes and namely double-positive cells occurred before the age of 3 months in Lurcher mice, which was accompanied by thymus involution. Interestingly, this was not accompanied by significant differences in major T subset proportions in the peripheral lymphatic tissue. CONCLUSIONS: We interpret our observations as hallmarks of premature thymus ageing in heterozygous Lurcher mice with only a marginal effect in the periphery in early adulthood.

Aging↗

PubMed2000

Non-Fc receptor-binding humanized anti-CD3 antibodies induce apoptosis of activated human T cells.

Human trials in organ allografts have demonstrated that murine anti-CD3 mAbs are immunosuppressive. By mimicking Ag, anti-CD3 can produce T cell activation, anergy, or death. Activation of resting T cells in vivo results in dose-limiting cytokine release and is caused by Ab-mediated cross-linking of T cells and Fcgamma receptor (FcR)-bearing cells. With the goal of minimizing cytokine-induced toxicity, anti-CD3 have been engineered to lower Fc binding avidity. Preclinical murine studies have indicated that non-FcR-binding anti-CD3 can induce apoptosis of Ag-activated T cells. Since induction of T cell apoptosis may be an important mechanism of immunosuppression by anti-CD3, we tested whether Fc mutations affect the ability of anti-human CD3 to induce apoptosis of activated T cells. We compared wild-type murine anti-CD3, M291, and OKT3 and their humanized, FcR- and non-FcR-binding structural variants in quantitative assays of T cell apoptosis. Non-FcR-binding variants produced more sustainable phosphorylation of extracellular signal-regulated kinase-2, greater release of IFN-gamma, and more effectively caused activation-dependent T cell apoptosis. Non-FcR-binding variants dissociated more quickly from the T cell surface and caused less internalization of the TCR, which then remained available in greater abundance on the cell surface for signaling. Cross-linking of non-FcR-binding variants by antiglobulin enhanced TCR internalization and minimized induction of T cell apoptosis. We conclude that non-FcR-binding, humanized anti-CD3 have improved ability to induce apoptosis of activated T cells, presumably by allowing durable expression of the TCR and sustained signaling.

Adult↗

PubMed1991

Evidence that antibodies to cytomegalovirus and the T cell receptor (TCR)/CD3 complex may have common ligands.

Immunoglobulins derived from sera containing anti-antiidiotypic antibodies (Ab2) generated in renal transplant recipients after OKT3 monoclonal antibody therapy, as reported in our previous study (1), have now been proved to bind to several bands of T cell membrane lysates (TCML) in immunoblotting analyses ranging in molecular weight from 40 to 55 KD. These sera also blocked the expression of the ligand binding to WT31 in flow cytometry. WT31 is a MAb that recognizes a common determinant on the T cell receptor (TCR). Immunoglobulins from these sera suppressed the activation of normal peripheral blood T lymphocytes (PBT) induced by OKT3. All patients (7/32) who developed this Ab2 had distinct culture-proved cytomegaloviral infections. In further immunoblotting studies, alpha F1, another MAb recognizing the framework of the TCR alpha chain, more deeply inserted in the T cell membrane, also showed binding to protein bands of cytomegalovirus pellet lysates derived from virus-infected embryonic fibroblasts. In addition, alpha F1 showed positive binding to several ligands in the membrane lysate of CMV-infected, but not noninfected MRC-5 cells. An anti-CMV MAb recognizing late nuclear antigen (LAb), also strongly bound to a approximately 50 KD band of TCML and several bands (approximately 34, approximately 40, and approximately 50 KD) of H33HJAJ1 (human T leukemia) cell lysate. Furthermore, alpha F1 immunoprecipitated a approximately 96 KD ligand of CMV-infected MRC5 lysate that had the same electrophoretic mobility as one of the proteins precipitable with LAb. Both LAb and alpha F1 also showed positive binding to paraformaldehyde-fixed and Triton X-100-permeabilized PBT in flow cytometry. Sera containing Ab2 blocked alpha F1 binding to acetone-fixed cytofuged PBT preparations on slides. Moreover, both alpha F1 and LAb inhibited mitogen-stimulated lymphocyte activation in vitro. These data support the notion that T cell functional abnormalities associated with CMV infection observed after treatment of transplant recipients with anti-T cell monoclonals might be caused by binding to T cell ligands by a variety of crossreacting human Igs operative in a regulatory network. Confirmatory evidence is the effect of MAbs generated against CMV virion epitopes crossreacting with T cell ligands, and vice versa.

Antibodies, Monoclonal↗

PubMed1999

Peroxynitrite inhibits T lymphocyte activation and proliferation by promoting impairment of tyrosine phosphorylation and peroxynitrite-driven apoptotic death.

Peroxynitrite (ONOO-) is a potent oxidizing and nitrating agent produced by the reaction of nitric oxide with superoxide. It readily nitrates phenolic compounds such as tyrosine residues in proteins, and it has been demonstrated that nitration of tyrosine residues in proteins inhibits their phosphorylation. During immune responses, tyrosine phosphorylation of key substrates by protein tyrosine kinases is the earliest of the intracellular signaling pathways following activation through the TCR complex. This work was aimed to evaluate the effects of ONOO- on lymphocyte tyrosine phosphorylation, proliferation, and survival. Additionally, we studied the generation of nitrating species in vivo and in vitro during immune activation. Our results demonstrate that ONOO-, through nitration of tyrosine residues, is able to inhibit activation-induced protein tyrosine phosphorylation in purified lymphocytes and prime them to undergo apoptotic cell death after PHA- or CD3-mediated activation but not upon phorbol ester-mediated stimulation. We also provide evidence indicating that peroxynitrite is produced during in vitro immune activation, mainly by cells of the monocyte/macrophage lineage. Furthermore, immunohistochemical studies demonstrate the in vivo generation of nitrating species in human lymph nodes undergoing mild to strong immune activation. Our results point to a physiological role for ONOO- as a down-modulator of immune responses and also as key mediator in cellular and tissue injury associated with chronic activation of the immune system.

Apoptosis↗

PubMed1994

CD8 requirements for negative selection events are directly related to the TCR-antigen interaction.

Positive selection of class I-restricted T cells has been suggested to always require the surface expression of CD8 molecules on CD4+8+ thymocytes, whilst negative selection was found to be differentially dependent, relating to the antigen being engaged by the T cell receptor (TCR). We have studied the CD8-dependency of positive and negative selection using two TCR-transgenic (Tg) mice models, which both react against the same allo-antigen, H-2kb, back crossed with mice which are deficient for the expression of CD8. Whilst CD8 expression was always required for positive selection of cells expressing high levels of the Tg-TCR, events of negative selection were differentially dependent upon CD8, reflecting the CD8-dependency of the original CTL clones. For one TCR-Tg model (derived from a CD8-dependent CTL clone), deletion of CD4+8+ thymocytes was partially dependent upon the expression of CD8, though there was still selection against Tg-TCR positive CD4+ cells, which normally exit to the periphery expressing low levels of Tg-TCR. For the other model (derived from a CD8-independent CTL clone) negative selection was unaffected by the absence of CD8. For both models the CD4-8- Tg-TCR positive population was unaffected by the absence of CD8, including, for the CD8-independent model, reduced expression of the Tg-TCR/CD3 complex. These results suggest that CD8 expression may be a prerequisite for positive selection, whilst negative selection events can occur in the absence of CD8, depending directly upon the TCR-antigen interaction.

Animals↗

PubMed1999

Differences in P-glycoprotein-170 expression and activity between Crohn's disease and ulcerative colitis.

The clinical benefit of Cyclosporine A (CsA) in IBD is controversial. Drugs including CsA are substrates of the P-glycoprotein-170 (Pgp-170) cell surface pump. Although the mechanism of action of CsA is complex, we determined that Pgp-170 might be expressed differentially between these two diseases. Intra-epithelial, lamina propria and peripheral blood lymphocytes were stained with the antibody MRK-16, which recognizes the surface antigen Pgp-170. Functional activity was assayed using a Rhodamine dye efflux assay (Rh123). RT-PCR was used to detect Pgp-170 mRNA. Overall, less P-gp-170 surface expression was found on UC CD3+ intestinal lymphocytes compared to controls and Crohn's disease. A decrease in Pgp-170 activity was also measured using the Rh123 functional assay. Fewer CD8+ intraepithelial lymphocytes (IEL) (which intrinsically have more Pgp-170 function) were also found in UC. Furthermore, UC IEL P-gp expression was under the limit of detection by RT-PCR. Overall, greater and differential expression, function and mRNA for Pgp-170 was found in Crohn's disease compared to the UC and normal tissues analyzed.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2001

Enhanced proliferation and increased IFN-gamma production in T cells by signal transduced through TNF-related apoptosis-inducing ligand.

TNF-related apoptosis-inducing ligand (TRAIL, also called Apo2L), a novel member of TNF superfamily, induces apoptosis in transformed cell lines of diverse origin. TRAIL is expressed in most of the cells, and the expression is up-regulated in activated T cells. Four receptors for TRAIL have been identified, and there is complex interplay between TRAIL and TRAIL receptors in vivo. The actual biological function of TRAIL/TRAIL receptor is still not clear. Growing evidence has demonstrated that members of TNF superfamily transduce signals after engagement with their receptors. Cross-linking of TRAIL by plate-bound rTRAIL receptor, death receptor 4-Fc fusion protein enhanced T cell proliferation and increased IFN-gamma production in conjunction with immobilized suboptimal anti-CD3 stimulation in mouse splenocytes. The increase of T cell proliferation by death receptor 4-Fc was dose dependent, and this effect could be blocked by soluble rTRAIL proteins, indicating the occurrence of reverse signaling through TRAIL on T cell. The enhanced secretion of IFN-gamma mediated via TRAIL could be blocked by SB203580, a p38 mitogen-activated protein kinase-specific inhibitor. Thus, in addition to its role in inducing apoptosis by binding to the death receptors, TRAIL itself can enhance T cell proliferation after TCR engagement and signal the augmentation of IFN-gamma secretion via a p38-dependent pathway. This provides another example of reverse signaling by a member of TNF superfamily. In conclusion, our data suggest that TRAIL can itself transduce a reverse signal, and this may shed light on the biological function of TRAIL.

Animals↗

PubMed1997

Artificial-capillary-system development of human alloreactive cytotoxic T-lymphocytes that lyse brain tumours.

The production of alloreactive cytotoxic T-lymphocytes (CTL) for therapy of recurrent brain tumours was performed in the CELLMAX artificial capillary system composed of cell-culture modules containing cellulose acetate or cuprammonium rayon hollow fibres. Lymphocytes, obtained from the brain-tumour patient to be used for sensitization, were stimulated with OKT3 (anti-CD3) and interleukin-2 (IL-2) and inoculated into the extracapillary space of artificial capillary modules. For allogeneic CTL production, the expanded patient lymphocytes were harvested, irradiated and placed into a second artificial capillary system with allogeneic lymphocytes from a healthy donor. In a one-way mixed lymphocyte reaction, CTL developed in the presence of low-concentration IL-2 (60 i.u. of IL-2/ml). In 18-21 days the cell preparation usually displayed a predominantly CD3+, CD8+ phenotype, which consorted with the dual-labelled CD8/CD11a markers used to identify CTL. Chromium (Cr)-release assays demonstrated lysis of patient tumour in relation to allogeneic glioma; the response observed in cold-target-inhibition assays confirmed lysis of the relevant tumour by the CTL.

Antibodies, Monoclonal↗

PubMed1990

Distinct sequence of negative or positive selection implied by thymocyte T-cell receptor densities.

Recent evidence suggests that positive and negative selection of thymocytes bearing alpha beta T-cell receptors occurs during the predominant double-positive (CD4+CD8+) stage. But the sequence or stage at which positive or negative selection occurs during thymocyte maturation has not been well defined. Here we use transgenic mice to show that the CD4+CD8+ stage might be further subdivided into CD3lo (low) and CD3in (intermediate) stages. The CD3in stage could represent T cells that have been positively selected, as this stage is dependent on the presence of the appropriate major histocompatibility complex restriction element. In addition, we use two different tolerizing antigens to show that negative selection may occur either before or after this CD3in stage.

Animals↗

PubMed1992

Signaling function of reconstituted CD16: zeta: gamma receptor complex isoforms.

Natural killer cells express an Fc receptor for IgG (CD16) in association with disulfide-linked dimers composed of two homologous subunits: the zeta chain of the T cell antigen receptor complex and the gamma chain of the mast cell/basophil Fc receptor for IgE. The ability of zeta and gamma to transduce CD16-mediated activation signals was compared by reconstituting distinct CD16 receptor isoforms composed of various combinations of zeta- and gamma-containing dimers. Stably transformed non-hematopoietic and hematopoietic cell lines were established that expressed chimeric molecules comprising the extracellular domain of CD16 joined to the transmembrane and intracellular domains of zeta or gamma. Reconstituted CD16 receptor complexes triggered Ca2+ influx, tyrosine phosphorylation, and IL-2 production in stable transformants of the Jurkat T cell line. However, cross-linking of the CD16/gamma chimera induced a specific pattern of tyrosine phosphorylation and was more efficient at signal transduction than a CD16, zeta-zeta complex, suggesting that zeta and gamma cytoplasmic domains may be coupled to distinct tyrosine kinase pathways that differentially regulate CD16-mediated activation signals. By contrast, both CD16/zeta and CD16/gamma chimeric molecules were not functional in stable transformants of the fibroblast Chinese Hamster Ovary cell line, indicating a requirement for downstream signaling components present in hematopoietic cells. Finally, the zeta transmembrane domain appears to preferentially associate with CD16 rather than the CD3:TCR complex, suggesting that a hierarchy of molecular interactions governs NK and T cell differentiation.

Animals↗

PubMed1993

Induction of activation-driven death (apoptosis) in activated but not resting peripheral blood T cells.

Signaling via the CD3/TCR complex induces programmed cell death (apoptosis) in immature thymocytes and transformed T lymphocytes (hybridomas or leukemic cells). Accumulating evidence indicates, however, that apoptosis can be triggered also in mature peripheral T cells. Here we show that a significant fraction of cells of a given IL-2-dependent TCR-alpha beta + clone or polyclonal short term line is killed when cultured for 20 h in the presence of PHA, anti-CD3 (OKT3), or anti-TCR (BMA031) mAb. Apoptosis can be triggered by these stimuli in CD4+, CD8+, and CD4-CD8- (double-negative) TCR-alpha beta+ clones. Activation-driven cell death (as quantified by propidium iodide staining and FACS analysis) is associated with fragmentation of DNA into oligonucleosomal bands of approximately 200 bp. Although freshly isolated peripheral blood T cells are largely resistant to apoptosis, the sensitivity to anti-CD3/TCR mAb or PHA-triggered cell death gradually increases upon activation and IL-2-dependent culture of T cells, and reaches a plateau level after 15 to 20 days. These data indicate that stimuli that activate resting T cells initiate death by apoptosis in activated T cells. The implications of these results for the regulation of cellular immune responses and the establishment of peripheral tolerance will be discussed.

Apoptosis↗

PubMed1993

Vasoactive intestinal peptide inhibits interleukin (IL)-2 and IL-4 production through different molecular mechanisms in T cells activated via the T cell receptor/CD3 complex.

The neuropeptide vasoactive intestinal peptide (VIP) has been reported previously to inhibit cell proliferation and interleukin (IL)-2 production in mitogen-stimulated T lymphocytes. In physiological conditions, T lymphocytes are specifically activated by antigen-binding through the T cell receptor (TCR). Here we report on the effect of VIP and related peptides on IL-2 and IL-4 production of murine T lymphocytes stimulated through the TCR. VIP inhibited IL-2 and IL-4 production (both at the level of protein concentration and biological activity) by unfractionated spleen cells or purified CD4+ T cells stimulated with either anti-CD3 monoclonal antibodies (mAbs) or with anti-CD3 mAbs plus phorbol esters. The inhibition was dose-dependent, and specific, since structurally related peptides such as secretin and glucagon had little or no inhibitory activity. VIP inhibited IL-2 and IL-4 production through different molecular mechanisms. IL-2 production was regulated at a transcriptional level through the downregulation of IL-2 mRNA, whereas the production of IL-4 was modulated at a posttranscriptional level.

Animals↗

PubMed2006

Modulation of antigen-specific T cell response by a non-mitogenic anti-CD3 antibody.

Suppression of T cell response is the key to enhance graft survival and control autoimmune diseases. A mitogenic anti-CD3 monoclonal antibody (mAb), OKT3, has been used for decades to control acute rejection in organ transplantation. Although effective, the clinical use was limited by its side effects, such as cytokine release mediated by T cell activation. A low mitogenic humanized OKT3 with reduced FcR-binding (hgammaOKT3 Ala-Ala) was generated and tested in several clinical studies. Although hgammaOKT3 Ala-Ala demonstrated maintained efficacy and better safety it still activated T cells. To investigate if a non-mitogenic anti-CD3 mAb can be equally effective in immune suppression, a chimeric non-FcR-binding anti-mouse CD3 mAb (anti-CD3 IgG2a Ala-Ala) was generated. Unlike the hgammaOKT3 Ala-Ala, the mouse IgG2a Ala-Ala anti-CD3 mAb did not induce T cell activation as measured by proliferation, cytokine production and apoptosis. Nevertheless, the IgG2a Ala-Ala anti-CD3 mAb was equally effective in the inhibition of antigen-specific CD4+ T cell activation in vitro to that of the mitogenic anti-CD3 mAb (Anti-CD3 IgG2a). In vivo, the IgG2a Ala-Ala anti-CD3 mAb only induced transient reduction of peripheral and spleen T cells and did not trigger detectable cytokine release. Nonetheless, this non-mitogenic anti-CD3 mAb significantly prolonged islet graft survival as effectively as the mitogenic anti-CD3 mAb in an allogenic islet transplantation model. These results demonstrated that a non-mitogenic anti-CD3 mAb could be used as an effective immune modulator. It may also indicate that a true non-mitogenic version of OKT3 could further improve its safety profile for clinical use.

Animals↗

PubMed1995

Negative transcriptional regulation in anergic T cells.

Anergy is a mechanism of T-lymphocyte tolerance induced by antigen-receptor stimulation in the absence of costimulation, whereby T cells exhibit a defect in antigen-induced transcription of the interleukin 2 (IL-2) gene. Here we present evidence for a mechanism of negative IL-2 gene regulation in anergic T cells. High amounts of binding activity to the negative regulatory element A (NRE-A) of the IL-2 promotor were detected in nuclear extracts from human T cells shortly after induction of anergy. Rapid induction of this nuclear complex is blocked by cyclosporin A and is found to be independent of protein synthesis. Plasmid DNAs, containing either the human phorbol 12-myristate 13-acetate-responsive element (PRE) or both NRE-A and PRE, were used as template for in vitro transcription assays in the presence of T-cell nuclear extracts. Under these conditions nuclear extracts from both anergic and rested T-cell clones, after crosslinking of CD3 and CD28, induced transcription of plasmids containing only PRE. However, when plasmids containing NRE-A and PRE were used, transcription was only induced by nuclear extracts from rested but not anergic T cells. These findings suggest the functional relevance of transcriptional repression of the IL-2 gene in anergic T cells.

Antigens, CD↗

PubMed1991

Signal transduction by the CD2 antigen in T cells and natural killer cells: requirement for expression of a functional T cell receptor or binding of antibody Fc to the Fc receptor, Fc gamma RIIIA (CD16).

Crosslinking of CD2 antigen on T lymphocytes and natural killer (NK) cells leads to a rise in cytoplasmic-free Ca2+ concentration ([Ca2+]i). However, CD2 seems unlikely to interact directly with the second messenger pathways since signaling via CD2 is poor in T cells that lack the T cell receptor (TCR) and is absent in L cells or insect cells that express CD2. In contrast, NK cells that are also TCR- can be triggered via CD2, but it is unclear as to whether the CD16 Fc receptor (FcR) may facilitate this effect. The CD16 transmembrane molecule is expressed in a complex with the zeta homodimer or the zeta/gamma heterodimer and these dimers are also associated with the TCR complex. Thus, it seemed that zeta chains may provide the link between signaling on NK cells and T cells. This could be tested on TCR- cells since when CD16 is transfected into T cells it is expressed in a complex with TCR zeta homodimer or the zeta/gamma heterodimer. At first, potentiation of CD2 signaling was seen on TCR- Jurkat cells expressing CD16, but this was found to be dependent on trace levels (1%) of IgG in F(ab')2 antibody preparations. With pure F(ab')2, the effect was lost. Signaling on a rat NK cell line was also re-examined with F(ab')2 antibodies that had no IgG contamination, and again no signal transduction via CD2 was seen. We thus conclude that there is no clear evidence for potent signaling via CD2 on cells that lack a TCR complex and that TCR zeta chain expressed at the cell surface is not sufficient to potentiate signaling via CD2 as measured by an increase in [Ca2+]i.

Animals↗