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At least 19 recordsLinked to original sources
PubMed1979

Studies on B-cell memory. II. T-cell independent antigen can induce B-cell memory.

Both athymic nude mice and normal mice primed with a T-cell independent antigen, i.e. dinitrophenylated dextran (DNP-DE), at a sub-immunogenic dose, produced very poor anti-DNP responses to a later challenge with the same antigen. B-cell memory was expressed, however, as an enhanced IgM response after the challenge of the DNP-DE-primed mice with the T-cell dependent antigen (dinitrophenylated haemocyanin, DNP-KLH) in the presence of functional T-cells. Moreover, DNP-DE-primed spleen cells also revealed an enhanced IgM response after adoptive transfer into irradiated recipients and challenge with DNP-DE. The injections of DNP-DE-primed nude mouse serum into unprimed mice resulted in the reduction of anti-DNP response to the immunization with DNP-DE. These results indicate that (a) T-cell independent DNP-DE causes the differentiation of B cells not only into antibody-forming cells but also into memory cells, (b) these memory cells can be triggered in situ by the T-cell dependent DNP-KLH in the presence of helper T cells but not by T-cell independent antigen, and (c) some humoral factor(s) induced by DNP-DE-priming seems to interfere with the expression of B-cell memory only when challenged with T-cell independent DNP-DE.

Animals↗
PubMed1976

Comparative studies on the actions of antigen and polyclonal B-cell activator in differentiation and proliferation of B-cells and B memory cells.

Using the capsular polysaccharide of Klebsiella pneumoniae (CPS-K) as a polyclonal B-cell activator (PBA) and sheep red blood cells (SRBC) as a T cell-dependent antigen, we compared the ability of PBA and antigen to differentiate (generate antibody-forming cells, AFC) and proliferate (generate immunological memory) virgin B cells and B memory cells. In vitro CPS-K induced the differentiation of IgM virgin B cells, IgM B memory cells and IgG B memory cells to AFC, as well as or better than SRBC. The differentiation of B memory cells to AFC by CPS-K did not require the participation of macrophages or T cells, whereas the action of SRBC depended strictly upon the helper actions of these cells. The responsiveness to CPS-K and SRBC of normal and antigen-primed spleen cells as judged by anti-SRBC PFC responses in vitro was markedly decreased after stimulation of virgin B cells and B memory cells in vivo by CPS-K injection into normal or primed mice but greatly increased after the injection of SRBC. The decrease in the responsiveness to CPS-K of spleen cells from mice treated with CPS-K appeared principally due to exhaustion of the functions of B cells and B memory cells. From the present data it has been concluded that the signals required for the differentiation and proliferation of B cells of B memory cells are different from each other, the signal for differentiation being provided by either antigen (SRBC) or PBA (CPS-K), while the signal for proliferation only by antigen.

Animals↗
PubMed1977

The generation of memory cells. I. The role of C3 in the generation of B memory cells.

Adult thymectomized, repopulated mice were chronically depleted of circulating C3 by treatment with cobra venom factor after primary immunization with dinitrophenylated haemocyanin (DNP-KLH). This treatment totally abrogated the development of B-cell memory in such mice, as assayed by a co-operative lymphocyte transfer. The failure of memory development appeared to involve impaired precursor proliferation following priming. It was further shown that the localization of DNP-KLH in splenic lymphoid follicles is both antibody and C3-dependent; thymus-deprived mice make sufficient antibody to DNP-KLH to effect follicular localization of the antigen. On the basis of these and earlier observations we suggest that the development of B-memory cells involves the formation of antigen-antibody-C3 complexes on dendritic cells in lymphoid follicles. C3 may serve to stabilize the antigen bridge between dendritic cells and virgin precursors. In complete contrast, C3 depletion had little effect on the functional expression of primed B cells, thus suggesting that only the early stages of B-cell triggering are C3 dependent.

Animals↗
PubMed1978

The generation of memory cells. II. Generation of B memory cells with preformed antigen-antibody complexes.

Mice were immunized with preformed complexes of dinitrophenylated haemocyanin (DNP-KLH) and anti-DNP or anti-KLH antibodies, and subsequently assayed for the generation of B memory (BM) cells. Complexes formed at equivalence or in slight antigen excess were far more effective than antigen alone in generating memory: as little as 100 ng DNP-KLH-anti-DNP produced substantial B cell priming. Anti-carrier and anti-hapten antibodies were equally effective. Complexes generated memory more rapidly than antigen alone, and the adjuvant effect was not simply due to aggregation of the antigen. Optimal priming by complexes required the integrity of the Fc portion of the antibody: F(ab')2 antibody fragments were less effective. The capacity of complexes to prime BM cells was abrogated by depriving mice of C3. C3 was also required for localization of complexes within splenic lymphoid follicles; complexes made with F(ab')2 localized in follicles, but less efficiently than those made with intact antibody. These results extend earlier findings (Klaus & Humphrey, 1977) and strongly suggest that the generation of BM cells involves the C3-dependent localization of antigen-antibody complexes within lymphoid follicles and strengthen the concept that germinal centres are the birthplace of BM cells.

Animals↗
PubMed1977

B memory cells in the thymus: part of the pool of potentially circulating memory cells.

Immunization of mice with sheep red blood cells (SRBC) or Escherichia coli lipopolysaccharide (LPS) induces the appearance of B memory cells in the thymus. In this paper the origin of these B memory cells was investigated. Therefore, mice primed with either SRBC or LPS 6 months previously and nonprimed mice were joined for parabiosis. Four weeks later the parabiotic mice were separated from each other. Another 3 weeks later thymus cells from the primed and nonprimed mice were transferred separately into lethally irradiated mice in order to determine the adoptive PFC response. It was found that the 4-week period of parabiosis could account for the appearance of a distinct population of B memory cells in the thymus of the nonprimed mice. This result suggest that the B memory cells which appear in the thymus belong to the pool of potentially circulating memory cells.

Animals↗
PubMed1979

Generation of memory cells. III. Antibody class requirements for the generation of B-memory cells by antigen--antibody complexes.

Immunizing mice with preformed antigen--antibody complexes is a highly effective means of generating B-memory cells. In the present study we have compared the capacity of mouse anti-dinitrophenyl (DNP) IgM, IgG1, IgG2 and IgA antibodies to generate DNP-specific memory, when given in complex with antigen (DNP-KLH: keyhole limpet haemocyanin). Two monoclonal IgM antibodies exerted no adjuvant effect, whereas a monoclonal IgA antibody was effective, IgG2 antibodies were a more powerful adjuvant than IgG1, regardless of whether anti-DNP or anti-KLH antibodies were used. Furthermore, the capacity of DNP-KLH--antibody complexes to localize in splenic lymphoid follicles could be ranked IgG2 greater than IgG1 greater than IgA; IgM complexes did not localize in follicles. These results correlate well with data (presented elsewhere) on the capacity of these different antibodies to activate mouse complement, and confirm that C activation is an essential requirement for both follicular localization of immune complexes, and for the generation of B-memory cells. Although activation of the alternative complement pathway is sufficient to effect both processes, the results with IgG2 antibodies raise the possibility that classical pathway activation may be more effective.

Animals↗
PubMed1979

Studies on B-cell memory. I. Generation and exhaustion of B-cell memory by thymus-dependent antigen in T-cell depleted mice.

Mice depleted of T cells by adult thymectomy, X-irradiation and reconstitution with syngeneic bone marrow cells, either untreated or treated with anti-Thy-1 serum and complement, were immunized intensively with alum-precipitated bovine serum albumin (AP-BSA) along with or without bacterial lipopolysaccharide (LPS), but no significant anti-BSA antibody response was detected. Priming of the T-cell depleted mice, however, either by a single injection of AP-BSA plus LPS or by multiple injections of AP-BSA without LPS, resulted in the generation of immunological memory. A single injection of AP-BSA without LPS was ineffective. The memory required the aid of syngeneic T cells to be recalled by the challenge with AP-BSA plus LPS. On the other hand, multiple injections of AP-BSA plus LPS did not cause the generation of memory and the response of these mice to the challenge was lower than that of unprimed control mice. These results suggest that (1) the anti-BSA response is highly dependent on the helper function of T cells, (2) the degree of T-cell requirement for the memory generation is very low, and (3) priming with too much strong stimulation in the absence of functional T cells leads to the suppression or abortion of previously generated immunological memory.

Animals↗
PubMed1976

Immunoglobulin M receptors on memory cells of immunoglobulin G antibody-forming cell clones.

The memory cells of two antibody-forming cell clones had receptors of the IgM class, even though the clones had been producing IgG1 or IgG2a anti-2,4-dinitrophenyl antibodies for 9-15 months previously (on exposure to antigen). Thus a phenotypic switch in heavy chain constant region evidently occurred after re-exposure of these memory cells to antigen. To show that, we first removed the clonal cells' surface immunoglobins by "capping" and "stripping", with class- or subclass-specific antisera. Then, to assay their remaining receptor activity, the cells were incubated with antigen in vitro, washed and transferred (together with carrier primed cells) to irradiated recipients, and their antibody responses to this in vitro boost were assayed by iselectric focusing. Pretreatment with anti-mu serum, as well as with anti-Fab(kappa), prevented the responses of the IgG1 and IgG2a clones to an in vitro boost, while anti-gamma1 and anti-gamma2a antisera had no effect. An antiserum to the putative mouse IgD also had no effect. The anti-mu serum failed to react with the IgG1 and IgG2A clonal serum antibodies in the test tube. Some other contaminating clones were suppressed completely only by the anti-Fab serum. This result strongly suggests that switching in class commitment may occur during the differentiation of memory cells to antibody producers, and may therefore be antigen-dependent. It also implies that some apparently naive cells with surface IgM may, in reality, be B memory cells.

Animals↗
PubMed1976

Two stages of B-cell memory development with different T-cell requirements.

We present evidence here for two stages in B-memory cell development, the first of which is T independent and the second T dependent. For these studies, we use a new type of T-deficient mouse (allotype suppressed) which specifically lacks T-helper activity (Th) for a subset of memory B cells responsible for approximately 10% of the overall IgG antibody response. We have shown elsewhere that these mice (SJL X BALB/c hybrids suppressed for Ig-1b) lack Th capable of helping Ig-1b memory cells, although they have normal Th activity for all other IgG memory B cells. This selective Th deficiency allows study of the effects of T depletion on memory development and avidity maturation of one population of B cells under conditions where the bulk of the immune response in the animal is proceeding normally, thus obviating environmental problems due to secondary effects of T depletion. With this sytem, we show that after a single priming dose of 2,4-dinitrophenyl-keyhole limpet hemocyanin, the memory B-cell pool in suppressed and nonsuppressed donors is indistinguishable with respect to magnitude and avidity of the response for all IgG antibodies produced, including Ig-1b antibody, despite the fact that expression of Ig-1b memory cells is prevented in intact Ig-1b-suppressed mice by the absence of Th capbale of cooperating with these memory cells. We have shown elsewhere that virtually all of the Ig-1b memory is carried by Ig-1b bearing cells. In contrast with the lack of suppressor T-cell effect on initial Ig-1b memory cell development, our data show that continued Ig-1b memory development is selectively impaired in suppressed mice. When primed mice are boosted repeatedly with the priming antigen, the average avidity of most of the IgG memory cells increases over 100-fold while there is no avidity increase in the Ig-1b component. To explain these data, we suggest that the development of high avidity memory occurs in two stages. The first stage, which occurs as a result of primary antigenic exposure, is the creation of a pool of IgG-bearing memory cells with a relatively low average avidity for the antigen. The appearance of these first stage memory cells does not require help from (post-thymic) Th, although Th are required for the expression of these memory cells (antibody production). The second stage of B-memory development requires both further antigenic stimulation and B-memory cell interaction with competent Th. This is a continuing process in which the number of memory cells in the pool remains relatively constant but the average avidity of these cells increases with continued antigenic exposure.

Animals↗
PubMed1978

Competition of the actions of antigen and polyclonal B-cell activator in the induction and amplification of B-memory cell function.

Using the capsular polysaccharide of Klebsiella pneumoniae (CPS-K) as a polyclonal B-cell activator (PBA) and sheep red blood cells (SRBC) as a T-dependent antigen, the correlation of the actions of PBA and T-dependent antigen on B cells in induction and amplification of immunological memory was studied. B-memory cell function, as judged by anti-SRBC responsiveness in vitro of spleen cells of CPS-K, was amplified by the secondary injection of SRBC into SRBC-primed mice, whereas it was decreased markedly by injection of CPS-K. When CPS-K was injected simultaneously with, or 1 or 2 days before the secondary injection of SRBC, B-memory cell function was also decreased markedly. On the other hand, CPS-K did not inhibit induction of B-memory cell function when injected simultaneouly with the primary injection of SRBC. However, CPS-K inhibited induction of B-memory cell function when injected 3 days before the primary injection of SRBC. The inhibition by CPS-K of amplification of B-memory cell function in response to SRBC when CPS-K was injected simultaneously with the secondary injection of SRBC occurred markedly in mice primed with SRBC 8 days or longer before the secondary injection, whereas it was not detectable in mice primed 3 days before. It is concluded that the CPS-K-mediated signal and the SRBC-mediated signal act competitively on the same subpopulations of B cells in induction and amplification of memory, and that the susceptibility of B cells to the CPS-K-mediated negative signal changes correspondingly with their maturation stage.

Animals↗
PubMed1975

The role of T cells in IgG production; thymus-dependent antigens induce B cell memory in the absence of T cells.

B cell memory was shown to develop in congenitally athymic (nu/nu) mice after injection with small amounts of thymus-dependent antigens, in particular heterologous serum proteins, such as fown gamma-globulin (FGG) or DNP-bovine-serum albumin (DNP-BSA). Large doses of proteins (10 mg) tended to produce a specific B cell unresponsiveness, although there was still some evidence of B cell priming. The antigen did not have to be in a multivalent form to interact with B cell so as to induce immunologic memory or tolerance. In contrast to the induction of B cell memory, the production of IgG antibody in this system was found to be strongly T cell dependent. Thymus-independent antigens like LPS or POL with pronounced adjuvant effects on IgG production in normal or surgically thymectomized mice, could not replace T cells in allowing an IgG response against thymus-dependent antigens in congenitally athymic mice. However, the action of T cells once activated is likely to be non-antigen-specific, since it was shown that supernatants of antigen-activated-syngeneic T cells stimulated IgG production in cultures of primed B cell populations non-antigen-specifically.

Animals↗
PubMed1977

Early kinetics of B cell memory and the influence of T cells on the expression in vitro.

To study the early kinetics of B cell memory to sheep erythrocytes mouse spleen cells were cultured after short priming times in vivo. The influence of T cells on the expression of memory in vitro was investigated by treatment with anti-theta serum. Within 48 hours of in vivo priming part of the B cell population can differentiate into cells capable of IgG production after secondary antigen contact in vitro without the help of T cells. The presence of antigen was required for the in vitro development.

Animals↗
PubMed1977

Secondary IgG responses to type 3 pneumococcal polysaccharide. III. T cell requirement for development of B memory cells.

Mice primed with a thymus-dependent form of Type 3 pneumococcal polysaccharide (S3), i.e. S3 coupled to erythrocytes (S3-RBC) produces S3-specific IgG antibody after secondary challenge with S3-RBC. When mice are depleted of T cells by treatment with anti-lymphocyte serum (ALS) at the time of priming, no IgG antibody is produced after secondary challenge. In order to determine the cellular basis for this phenomenon, various combinations of T and/or B cells from ALS-treated or normal primed mice were transferred to irradiated recipients prior to secondary challenge with S3-RBC. The results indicated that T cells were required at the time of priming with S3-RBC in order to (a) prevent the induction of tolerance in S3-specific B cells in mice primed with high doses of S3-RBC, and (b) induced differentiation of IgG-producing B cell precursors to Bgamma memory cells in mice primed with low doses of antigen.

Animals↗
PubMed1979

Detection of memory cells by chemical modification of the lymphocyte cell surface.

Stringent alloantigen requirements, necessary for the differentiation of human memory cells into specific secondary cytolytic T cells (2 degrees CTL), can be bypassed by chemical modification of memory cells with the mitogenic oxidising agent, galactose oxidase. Treatment of memory cells generated in a long-term primary mixed lymphocyte culture with neuraminidase and galactose oxidase (NAGO) results in the differentiation of memory cells into 2 degrees CTL. In contrast, treatment of unprimed cells with NAGO does not result in CTL production despite the proliferation resulting from such treatment.

Cell Membrane↗
PubMed1977

Quantitative studies on the precursors of cytotoxic lymphocytes. III. The lineage of memory cells.

In the course of a mixed lymphocyte culture, memory cells are produced which can give rise to a large secondary cytotoxic lymphocyte response on reexposure to the sensitizing alloantigen. We have studied the lineage of these memory cells using a clonal assay for precursors of cytotoxic T lymphocytes (CLP). Our data provide conclusive evidence that individual CLP, upon stimulation with alloantigens, gives rise to clones which contain memory cells of the same specificity as the CLP. Only half of the clones that responded in the primary stimulation could be reactivated upon exposure to the original priming alloantigen.

Animals↗
PubMed1978

Idiotype-specific T helper cells are required to induce idiotype-positive B memory cells to secrete antibody.

We have tested the proposition that induction of certain sets of B cell clones to produce antibody requires a signal from T helper cells that recognize idiotypic determinants expressed on Ig receptors of the relevant B cell clones. The approach is based on the analysis of T cell populations required to induce B cells to secrete anti-arsonate antibodies that are marked by a cross-reactive idiotype (CRId). crid+ anti-azophenyl arsonate (Ar) antibodies are produced in A/J strain mice after immunization with Ar keyhole limpet hemocyanin and represent 20--70% of the total anti-Ar antibody response. These studies indicate that antibody secretion by idiotype+ B memory cells requires two signals: one provided by "carrier"-specific Ly-1 cells, and a second delivered by idiotype-specific Ly-1 cells. Both signals are required for optimal induction of idiotype+ B memory clones.

Animals↗
PubMed1976

Clonal dominance and the preservation of clonal memory cells mediated by antigen-antibody.

Selected B-cell clones and their well characterized monoclonal antibody products were used to analyse the role of antibody in clonal dominance and the regulation of memory cell supplies. The experimental design was to permit contact between spleen cells and antigen in vitro, and to administer antibody to DNP prior to or following cell transfers into irradiated recipients. The anti-hapten response was strongly suppressed by the clone's own antibody or higher affinity antibody administered on day 0. Antigen-antibody inhibited memory cell generation. The suppressive effect was temporary, and reversible with time and further antigen and the same clone could be induced to produce antibody again, analysed by isoelectric focusing. We were therefore not dealing with clonal deletion. Change in the source of clonal anti-hapten excluded possible effects of antibody to carrier protein or idiotypic determinants in this system. The timing of antibody administration indicates that clones already triggered in the first 4 days after antigen contact could not be suppressed by antibody. Passive antibody to DNP only suppressed when both B and T cells had been permitted contact with hapten-carrier protein. Alteration of the carrier protein enabled us to study the effect of antigen-antibody on B and T cells separately. B cells binding antigen and antibody to hapten were triggered more efficiently by fresh T cells recognizing the carrier protein than after antigen uptake alone. Antibody to DNP suppressed only when both B and T cells had taken up hapten-protein, suggesting that antigen-antibody acts centrally at the level of both B memory cells and T helper cells. This reversible antigen-antibody blockade appears to favour the preservation of a pool of long-lived memory cells rather than the priming of new clones developing from short lived precursor cells; clonal dominance ensues.

Animals↗