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PubMed2001

Presence of a population of CD20+, CD38- B lymphocytes with defective proliferative responsiveness in the synovial compartment of patients with rheumatoid arthritis.

OBJECTIVE: To provide a comprehensive understanding of the humoral immune response that takes place at the site of inflammation in rheumatoid arthritis (RA), we studied the functional properties of synovial B cells. In particular, the response to various modes of mitogen stimulation was investigated. METHODS: Purified synovial fluid (SF) B cells were cultured in the presence of CD40 ligand (CD40L)-expressing fibroblasts and cytokines, activated T cells, or phorbol myristate acetate (PMA)/ionomycin. Proliferation was determined by 3H-thymidine incorporation. Release of intracellular calcium was studied by flow cytometry. RESULTS: The inflamed joints of RA patients contained a population of CD20+,CD38- B cells with dramatically impaired mitogen responsiveness. Although the Ig-producing capacity was intact, these cells failed to proliferate in response to (a) CD40 in the presence of interleukin-2 (IL-2) and IL-10, (b) activated T cells, or (c) stimulation via the B cell receptor. Moreover, SF CD20+,CD38- B cells revealed a defective B cell receptor-induced Ca2+ influx, reminiscent of anergic B cells. Release of intracellular Ca2+ by ionomycin in the presence of the protein kinase C activator PMA did not restore the proliferative capacity. These findings indicate blockades in the proximal and distal intermediates involved in mitogen signaling. CONCLUSION: SF CD20+,CD38- B cells have functionally impaired proliferative responsiveness. The capacity of these cells to respond to activation by the production of Ig supports the notion that these cells might serve as Ig-producing effector cells and, as such, play a role in the pathophysiology of RA.

ADP-ribosyl Cyclase↗
PubMed1989

The expression and function of CD3 and CD5 in patients with primary Sjögren's syndrome.

We studied the expression and function of 2 cell surface markers that induce T cell activation, CD3 and CD5, in 19 patients with primary Sjögren's syndrome (SS). The expression of CD3+ lymphocytes was normal, but CD3 function was moderately reduced, as measured by anti-CD3-induced T cell proliferation. Anti-CD3-induced stimulation of T cell help for Ig production and non-major histocompatibility complex-restricted (natural) killing were normal. In contrast, there was reduced expression and function of the CD5 molecule on peripheral blood lymphocytes of the SS patients. The ratio of CD5+ to CD3+ lymphocytes was 0.45 in SS patients compared with 0.85 in normal subjects, indicating that the CD3+ cells are relatively CD5-deficient in SS patients. Anti-CD5 monoclonal antibody did not augment suboptimal anti-CD3 stimulation of whole peripheral blood lymphocytes or of purified T lymphocytes from SS patients, which indicated impaired functioning of the CD5 molecule. A significant impairment in proliferation was found in response to phorbol myristate acetate and to ionomycin in combination, suggesting defective intracellular signaling. Findings from serial studies of individual patients suggested that normal or low expression of CD5 on T cells can be stable over periods as long as 2 years. However, in 2 patients who required systemic therapy, a correction of the CD5 lymphocyte abnormality occurred in association with clinical remission, which suggests the potential reversibility of this condition. Our findings suggest a possible defect in intracellular signaling in primary SS, related in part to the CD5 molecule, which may provide a molecular explanation for the T cell hyporesponsiveness that is characteristic of this disease.

Antigens, Differentiation↗
PubMedDate not supplied

Luminol-amplified chemiluminescence activity in human monocytes: a comparison with the activity induced in granulocytes.

The characteristics of the luminol-amplified chemiluminescence (CL) induced in mononuclear phagocytes interacting with PMA, FMLP or ionomycin were determined. Azide reduced the CL activity by more than 80%, while superoxide dismutase and catalase had minor effect on the monocyte CL response. The sensitivity of the monocyte CL response, to the addition of extra peroxidase differed depending on the stimulus used. Furthermore, no direct correlation was obtained between the CL response and superoxide anion or hydrogen peroxide production. In comparison with the response in granulocytes, minor quantitative differences were observed. The mechanism for the light-generating reaction, seems to be the same in both cell types.

Adult↗
PubMed1988

Polymorphonuclear leukocyte locomotion is insensitive to lowered cytoplasmic calcium levels.

Chemotactic factors stimulate the rate of locomotion of polymorphonuclear leukocytes (PMNs). To investigate the importance of cytoplasmic calcium we have examined the ability of the chemotactic peptide N-formylnorleucyl eucylphenalanine (FNLLP) to stimulate the locomotion of PMNs whose cytoplasmic calcium levels were reduced by incubation in EGTA or in EGTA plus the calcium ionophores, ionomycin or A23187. Locomotion was assayed by migration through micropore filters and by time-lapse videomicroscopy. Cells in EGTA exhibited similar or slightly reduced rates of locomotion compared to cells in Hanks' balanced salt solution (HBSS). The peptide dose dependence for the stimulation of locomotion was similar in medium containing calcium or EGTA. The presence of 1 microM ionophore plus EGTA had no effect on the stimulation of locomotion by peptide. The presence of ionophores (1 microM) plus external calcium inhibited locomotion.

Animals↗
PubMed2001

Sodium-calcium exchanger (NCX-1) and calcium modulation: NCX protein expression patterns and regulation of early heart development.

Ouabain-induced inhibition of early heart development indicated that Na/K-ATPase plays an important role in maintaining normal ionic balances during differentiation of cardiomyocytes (Linask and Gui [1995] Dev Dyn 203:93-105). Inhibition of the sodium pump is generally accepted to affect the activity of the Na(+)-Ca(++) exchanger (NCX) to increase intracellular [Ca(++)]. These previous findings suggested that Ca(++) signaling may be an important modulator during differentiation of cardiomyocytes. In order to identify a connection between heart development and NCX-mediated Ca(++) regulation, we determined the embryonic spatiotemporal protein expression pattern of NCX-1 during early developmental stages. In both chick and mouse embryos, NCX-1 (the cardiac NCX isoform) is asymmetrically expressed during gastrulation; in the right side of the Hensen's node in the chick, in the right lateral mesoderm in the mouse. At slightly later stages, NCX-1 is expressed in the heart fields at comparable stages of heart development, in the chick at stage 7 and in the mouse at embryonic day (ED) 7.5. By ED 8 in the mouse, the exchanger protein displays a rostrocaudal difference in cardiac expression and an outer curvature-inner curvature ventricular difference. By ED 9.5, cardiac expression has increased from that seen at ED8 and NCX-1 is distributed throughout the myocardium consistent with the possibility that it is important in regulating initial cardiac contractile function. Only a low level of expression is detected in inflow and outflow regions. To substantiate a role for the involvement of calcium-mediated signaling, using pharmacologic approaches, ionomycin (a Ca(++) ionophore) was shown to perturb cardiac cell differentiation in a manner similar to ouabain as assayed by cNkx2.5 and sarcomeric myosin heavy chain expression. In addition, we show that an inhibitor of NCX, KB-R7943, can similarly and adversely affect early cardiac development at stage 4/5 and arrests cardiac cell contractility in 12-somite embryos. Thus, based upon NCX-1 protein expression patterns in the embryo, experimental Ca(++) modulation, and inhibition of NCX activity by KB-R7943, these results suggest an early and central role for calcium-mediated signaling in cardiac cell differentiation and NCX's regulation of the initial heartbeats in the embryo.

Animals↗
PubMed1986

Activation and proliferation signals in mouse B cells. VIII. Induction of DNA synthesis in B cells by a combination of calcium ionophores and phorbol myristate acetate.

Mouse B cells cultured with either phorbol myristate acetate (PMA), or with Ca2+ ionophores enter a transitional activated state, between quiescence (G0) and G1, but do not synthesize DNA. It is shown here that the combination of PMA plus the ionophore ionomycin induces resting B cells to synthesize DNA, but not to secrete antibody. B cells from CBA/N mice carrying the xid defect, and those from the lipopolysaccharide-unresponsive C3H/HeJ strain also respond to this combination. Suboptimal doses of the two stimuli synergize with B cell-stimulating factor 1 in promoting proliferation of resting B cells, but the co-mitogen does not substitute for type II B cell growth factor in the BCL1 lymphoma. Furthermore, (as predicted) the combination of these two agents does not induce the breakdown of inositol phospholipids in B cells. These data are consistent with the hypothesis that elevation of intracellular Ca2+ (by the ionophore), plus activation of protein kinase C (by PMA) leads to DNA synthesis in B cells. The combination of Ca2+ ionophore and PMA thus appears to essentially mimic the biochemical effects of ligation of surface immunoglobulin receptors on B cells, by providing the two second messengers normally emanating from the receptor-mediated breakdown of polyphosphoinositides.

Animals↗
PubMed1986

Early events in human B cell activation: metabolic pathways vary according to the first signal used.

The effects of the calcium channel blocking drug Verapamil and of palmitoyl-carnitine (PTC), an inhibitor of protein-kinase C activity, on human B cell activation were measured. Both Verapamil and PTC inhibited the B cell proliferation induced by costimulation with anti-mu antibody and with 3 different growth factors: interleukin 2, 20-kDa B cell growth factor and 50-kDa B cell growth factor. Both uridine and thymidine incorporation induced by costimulation with ionomycin and phorbol 12-myristate 13-acetate (PMA) were inhibited by Verapamil and PTC. In contrast, B cell proliferation was resistant to Verapamil (while being still inhibited by PTC) in two situations: when B cells were costimulated with PMA and growth factors and when B cells previously activated in vitro (by anti-mu antibody or PMA) were stimulated with growth factors. These results confirm that the late stage (G1----S transition) of B cell activation is independent of Ca2+ entry. More importantly, they show that the initial events induced by anti-mu antibody and by PMA are based on different biochemical pathways: PMA would act on a subpopulation of B cells which has already received an early signal of activation in vivo. This emphasizes the functional and biochemical heterogeneity of the G0 stage among circulating B cells.

B-Lymphocytes↗
PubMed1988

Effect of tumor promoter 12-O-tetradecanoyl-phorbol 13-acetate on CD 7 expression by T lineage cells.

Phorbol esters exert diverse effects on cellular activation and differentiation. CD 7, a differentiation antigen appearing early in T cell ontogeny, may be involved in the activation and differentiation processes. CD 7 was found to be rapidly down-regulated by 12-O-tetradecanoylphorbol 13-acetate (TPA) from mature T cell surface. The time course of CD 7 down-regulation was similar to that of other functionally important T cell antigens, CD 3 and CD 4. Within 2 h, TPA at 10 to 30 ng/ml induced a complete down-regulation of CD 7. Twenty-four hours later, the reappearance of CD 7 on TPA-treated cells was observed. This phenomenon was monocyte independent. In contrast, CD 7 expression on thymocytes was resistant to the effect of TPA. In addition, certain leukemic T cells were also resistant to TPA-induced CD 7 down-regulation. The mechanism underlying TPA-induced CD 7 down-regulation was investigated further. Synthetic diacylglycerol, sn-1,2-dioctanoylglycerol, which activates protein kinase C, did not induce down-regulation of CD 7 on mature T cells. Ionomycin, a calcium ionophore, did not down-regulate this antigen either. Thus, it is concluded that the processes of protein kinase C activation and/or cytosolic calcium influx are not sufficient for TPA-induced CD 7 down-regulation; other pathways induced by TPA may be responsible.

Antibodies, Monoclonal↗
PubMed1988

Division of human helper T cells into two sets on the basis of the induction of anti-tumor cytotoxicity by phorbol ester and calcium ionophore.

Fourteen noncytotoxic human helper T cell clones were examined for autocrine proliferative responses and cytotoxicity to tumor cells after stimulation with 12-O-tetradecanoylphorbol 13-acetate (TPA) and ionomycin (Io). Although all clones responded to alloantigen, they could be divided into two groups based on their proliferative response or lack of it to TPA/Io. Nonresponders could not be converted to responder status by addition of interleukin (IL) 1 or indomethacin to the cultures. Responder status did not correlate with any of the following properties of the clones: originating donor, recognitive specificity, B cell helper activity, proliferative response to IL 2 or 4, lymphokine secretory capacity or density of expression of antigen receptors, CD4 or HLA class II molecules. Responder status did, however, correlate with the ability of TPA/Io to induce major histocompatibility complex-unrestricted cytolytic activity directed towards natural killer-resistant tumor cells. These results divide human helper cells into two types on the basis of induction of anti-tumor cytotoxicity.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1988

Cross-linking of membrane IgM on B CLL cells: dissociation between intracellular free Ca2+ mobilization and cell proliferation.

It has been shown previously that chronic lymphocytic leukemia (CLL) B cells are frozen at different stages of activation with unique requirements for proliferation. Although most B CLL cells express surface IgM, anti-mu antibodies are able to trigger only some of them to proliferate and/or respond to B cell growth factor (BCGF) or interleukin 2 (IL2), as normal B cells. In this report we extend these observations using three different monoclonal antibodies (mAb) to human mu chain (one mitogenic in soluble form for normal B cells, the two others mitogenic only when coupled on Sepharose 4B beads). Cells from only 3 out of 11 B CLL patients proliferated in the presence of either mitogenic anti-mu. When the early events following surface Ig cross-linking, such as calcium mobilization (by flow cytometry on indo-1-labeled cells), were studied all three mAb in soluble form were able to induce a similar increase in the intracellular free calcium concentration ([Ca2+]i); analogous to [Ca2+]i rise after the mitogenic F(ab')2 anti-mu stimulation. This response was seen only in 8 out of the 12 CLL B cells studied. All B CLL cells, however, proliferate in response to a combination of phorbol ester 12,13-dibutyrate (PBt2) and ionomycin. Therefore, three patterns of response to sIg cross-linking by anti-mu could be distinguished: cells from 4 out of 12 cases proliferate and mobilize Ca2+ upon anti-mu triggering (behaving like resting B lymphocytes); in 4 other cases anti-mu lead to Ca2+ mobilization without cell proliferation; in the last 4 cases neither Ca2+ mobilization, IP3 generation (in the one case studied) nor cell proliferation are observed although these cells do proliferate directly in response to growth factors. Moreover, anti-mu stimulation in this group leads to increased proliferation in response to BCGF and IL2 suggesting an anti-Ig signaling independent of inositol phosphate metabolism. These results are interpreted in terms of differential anti-mu signaling on B cells at different stages of activation.

Antibodies, Anti-Idiotypic↗
PubMed1989

Pgp-1hi T lymphocytes accumulate with age in mice and respond poorly to concanavalin A.

Aging is associated with an accumulation of T cells functionally hyporesponsive to the effects of mitogens such as concanavalin A. Recent studies in mice and human have identified surface markers useful for distinguishing antigen-stimulated memory T cells from virgin T cells. In mice, memory T cells within the CD8+ cell population have been shown to express relatively high levels of the cell surface glycoprotein Pgp-1. On the theory that aging might diminish the supply of virgin thymic emigrants without compromising the production of memory T cells, we examined the proportion of Pgp-1hiCD4+ and CD8+ cells in the spleen, blood and lymph nodes of mice of varying age. We found a dramatic (2.5-fold) age-associated increase in the percentage of cells with the Pgp-1hi phenotype. By limiting dilution methods, the frequency of concanavalin A-responsive T cells was found to be significantly reduced in the Pgp-1hi cell pool, whether measured by interleukin 2-dependent proliferation, interleukin 2 production or generation of cytotoxic effectors. Pgp-1hi and Pgp-1lo T cells from young mice proliferate equally well when stimulated by optimal doses of phorbol myristate acetate and ionomycin suggesting that the poor responses to concanavalin A do not simply reflect low viability. Aging leads both to an increase in mitogen-hyporesponsive Pgp-1hi T cells, and also to lower responsiveness of cells in the Pgp-1hi subset.

Aging↗
PubMed1989

Selective induction of growth factor production and growth factor receptor expression by different signals to a single T cell.

Stimulation of lymphokine production and the expression of receptors for growth factors can be dissociated in AK-8, a line of CD4+, I-A-restricted, conalbumin-specific mouse T cells. When activated by antibodies specific for the T cell receptor (TcR; F23.1) or the CD3 complex (145-2C11) adsorbed to plastic culture wells, AK-8 cells produce lymphokines but are unable to proliferate. Proliferation takes place using the same stimuli upon addition of interleukin 1 (IL 1). Autocrine growth induced by anti-TcR, anti-CD3 or by antigen is dependent on IL 4 and not on IL 2 in this cell line, as shown by the effect of antibodies against IL 4 or the IL 2 receptor. Similarly to plastic-adsorbed antibodies, phorbol myristic acetate (PMA) or a combination of PMA and the calcium ionophore Ionomycin also induces secretion of growth factors without inducing proliferation, but in this case addition of IL 1 is ineffective in inducing AK-8 proliferation. When incubated with anti-TcR or anti-CD3 antibodies in soluble form these cells neither proliferate nor produce IL 4 even in the presence of IL 1. However, soluble antibodies in the presence of IL 1 induce enhanced expression of IL 2 receptors, as measured both by induction of responsiveness to exogenous IL 2 or flow cytometry analysis using anti-IL 2 receptor antibodies. These results show that the pathways for the activation of growth factor receptor expression and the induction of lymphokine secretion can be differentiated in this cell line using anti-TcR or anti-CD3 reagents in different physical forms. The transmembrane signals delivered by these different forms of anti-receptor antibody may allow an understanding of these distinct requirements for T cell growth.

Animals↗
PubMed1991

Differential regulation of gamma and delta T cell antigen receptor gene expression by phorbol esters and Ca2+ ionophores in the acute lymphocyte leukemia DND41 cell line.

We have investigated the role of two signal transduction pathways on the regulation of the gamma and delta T cell antigen receptor (TcR) gene expression, in the acute lymphocytic leukemic cell line DND41. Protein kinase C (PKC) activation, and intracellular free Ca2+ mobilization, initiated by phorbol esters and calcium ionophores, respectively, not only acted independently but, more interestingly, their effects were antagonistic, suggesting a role for these signals during T cell differentiation. The Ca2+ ionophore, ionomycin, increased the levels of intracellular free Ca2+ and induced the expression of the gamma and delta chains of the T cell antigen receptor in a concentration-dependent manner. The phorbol ester 12-myristate 13-acetate down-regulated the basal gamma TcR expression with marginal effect on delta TcR mRNA, but diminished the induction of both gamma and delta TcR, initiated by the Ca2+ ionophore. These antagonistic effects of the two arms of the phospholipase C-mediated signal transduction pathways, i.e. PKC activation and increased intracellular free Ca2+, were specific to the regulation of the gamma and delta TcR, since the same signals exerted a synergistic effect on the mRNA levels of interleukin 2 receptor. These data confirm our hypothesis that the antagonistic regulation on the gamma and delta TcR gene expression by phorbol esters and calcium ionophores occurs in the same cell, and stresses the biological significance of PKC activation and intracellular free calcium mobilization during intrathymic differentiation and selection.

Blotting, Northern↗
PubMed1991

Signaling requirements for the expression of the transactivating factor NF-AT in human T lymphocytes.

A protein called nuclear factor of activated T cells (NF-AT) binds to DNA sequences within the enhancer region of the interleukin 2 (IL 2) gene and appears necessary for both the inducibility and T cell specificity of IL 2 expression. IL 2 production is regulated by multiple signals including those generated via activation of the T cell antigen receptor complex (TcR/CD3), CD2 antigen, protein kinase C (PKC) or elevation of intracellular free calcium concentration ([Ca2+]i). We have, therefore, explored the role of these different stimuli in regulating the nuclear expression of NF-AT in human peripheral blood-derived lymphocytes. Results presented herein indicate that maximal expression of NF-AT in T cells requires at least two signals: PKC activation and TcR/CD3 or CD2 triggering, [Ca2+]i increases and TcR/CD3 or CD2 triggering. Data are presented that indicate that either the [Ca2+]i or PKC signal generated via the TcR/CD3 complex would not alone induce NF-AT expression, and that the TcR/CD3 complex probably regulates NF-AT expression because of its ability to regulate multiple intracellular signals in T cells, and not via any single biochemical event. The combination of CD2 mAb GT2/OKT11 used in the present study to trigger the CD2 antigen is able to act in synergy with phorbol 12,13-dibutyrate or ionomycin to induce NF-AT expression. However, these CD2 mAb do not elevate [Ca2+]i or activate PKC, suggesting that signals other than [Ca2+]i or PKC can regulate NF-AT expression in peripheral blood-derived T cells.

Antigens, CD↗
PubMed1993

Antigen-presenting human T cells and antigen-presenting B cells induce a similar cytokine profile in specific T cell clones.

One of the factors that may influence the cytokine secretion profile of a T cell is the antigen-presenting cell (APC). Since activated human T cells have been described to express major histocompatibility complex (MHC) class II molecules as well as costimulatory molecules for T cell activation, like e.g. ICAM-1, LFA-3 and B7, they might play a role as APC and be involved in the regulation of T-Tcell interactions. To define further the role of T cells as APC we tested their capacity to induce proliferation and cytokine production in peptide- or allospecific T cell clones and compared it with conventional APC, like B lymphoblasts (B-LCL) or HTLV-1-transformed T cells, or with non-classical APC, like activated keratinocytes or eosinophils. CD4+, DP-restricted T cell clones specific for a tetanus toxin peptide (amino acids 947-967) and CD4+, DR-restricted allospecific T cell clones produced interleukin (IL)-2, IL-4, tumor necrosis factor-alpha and interferon-gamma (IFN-gamma) after phorbol 12-myristate 13-acetate and ionomycin stimulation and a more restricted cytokine pattern after antigen stimulation. Dose-response curves revealed that the antigen-presenting capacity of activated, MHC class II+, B7+ T cells was comparable to the one of B-LCL. Both APC induced the same cytokine profile in the T cell clones despite a weaker proliferative response with T cells as APC. Suboptimal stimulations resulted in a lower IFN-gamma/IL-4 ratio. Cytokine-treated, MHC class II+ keratinocytes and eosinophils differed in the expression of adhesion molecules and their capacity to restimulate T cell clones. The strongly ICAM-1-positive keratinocytes induced rather high cytokine levels. In contrast, eosinophils, which express only low densities of MHC class II and no or only low levels of adhesion molecules (B7, ICAM-1 and LFA3), provided a reduced signal resulting in a diminished IFN-gamma/IL-4 ratio. We conclude that non-classical APC differ in their capacity to restimulate T cell clones, whereby the intensity of MHC class II and adhesion molecules (B7, ICAM-1) expressed seems to determine the efficacy of this presentation.

Antigen-Presenting Cells↗
PubMed1994

Reversal of hyporesponsiveness in lpr CD4-CD8- T cells is achieved by induction of cell cycling and normalization of CD2 and p59fyn expression.

T cells freshly isolated from the peripheral lymph nodes of autoimmune MRL lpr/lpr (lpr) mice contain a large proportion of functionally non-mature T cell receptor (TcR)-alpha beta+CD3+CD2-CD4-CD8- T cells displaying the B cell isoform of CD45, B220. These cells are hyporesponsive as defined by minimal interleukin-2 (IL-2) production and proliferation in response to stimulation. However, increased levels of inositol phosphates and a rapid mobilization of Ca2+ do occur upon stimulation of the TcR/CD3 complex. Furthermore, lpr CD4-CD8-T cells contain high levels of transcripts for the src-family tyrosine kinase p59fyn, and express a constitutively tyrosine-phosphorylated CD3-zeta chain. These features bear a certain resemblance to anergized T cells. These similarities are extended to show that culturing of lpr CD4-CD8- T cells in the presence of IL-2 in combination with phorbol 12-myristate 13-acetate and ionomycin initiates cell cycling and results in the gain of function; re-stimulation now yields IL-2-dependent proliferation in the absence of exogenous IL-2. In parallel with this gain in function, the population of cells obtained after 1 week in culture retains the TcR-alpha beta + CD4-CD8- phenotype, yet displays increased levels of CD2, decreased surface B220, and normal amounts of p59fyn-specific transcripts. These findings show that cell cycling is associated with the recovery of functional capabilities by lprCD4-CD8-T cells and is closely allied with surface CD2 expression. Thus, the hyporesponsiveness of lpr T cells is not a fixed state.

Aged↗
PubMed1994

Fas-based lymphocyte-mediated cytotoxicity against syngeneic activated lymphocytes: a regulatory pathway?

To investigate the possibility that Fas-based immune regulation and Fas-based T cell-mediated cytotoxicity (F-CMC) are causally related, we explored the latter in activated lymphocyte populations. These were shown to contain effector cells exerting cytotoxicity via an F-CMC mechanism which could be differentially triggered by PMA and ionomycin. F-CMC operated in trans, requiring an lpr (Fas) product on target cells and a gld product on effector cells. Activated lymphocyte populations were also shown to contain F-CMC target cells. Activated lymphocyte populations thus contained both effector and target F-CMC cells, which could lyse each other. Fas-based cytotoxicity can thus lead to the lysis of syngeneic activated lymphocytes, consistent with the possibility of its participation in the down-regulation of immune responses, and more generally offering a model of socially controlled, direct membrane-mediated cell death.

Animals↗
PubMed1994

Decreased expression of the ligand for CD40 in newborn lymphocytes.

Immune responses in newborn lymphocytes show a defect in isotype switching from IgM to IgG and IgA. Immunoglobulin isotype switching in B lymphocytes requires a contact-dependent signal from T lymphocytes which is delivered by the ligand for the B cell surface antigen CD40. We investigated the capacity of newborn lymphocytes to express the CD40 ligand and to undergo CD40 ligand-dependent immunoglobulin isotype switching. After stimulation by phorbol ester and ionomycin, newborn lymphocytes expressed markedly decreased amounts of CD40 ligand on their surface compared to normal adult lymphocytes. Northern blot analysis of mRNA derived from activated cord blood lymphocytes also revealed markedly decreased amounts of CD40 ligand mRNA. Decreased expression of CD40 ligand in newborn lymphocytes was associated with a severely decreased ability to undergo T cell-dependent immunoglobulin isotype switching. Newborn lymphocytes synthesized little or no detectable IgE in response to T cell-dependent stimulation by interleukin-4 but synthesized IgE in response to T cell-independent stimulation by CD40 monoclonal antibody and interleukin-4. These results indicate that decreased expression of CD40 ligand in newborn lymphocytes may be the underlying cause of deficient immunoglobulin isotype switching in newborns.

Blotting, Northern↗