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Results for “Memory T Cells”

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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↗

PubMed2014

Epigenomic analysis of primary human T cells reveals enhancers associated with TH2 memory cell differentiation and asthma susceptibility.

A characteristic feature of asthma is the aberrant accumulation, differentiation or function of memory CD4(+) T cells that produce type 2 cytokines (TH2 cells). By mapping genome-wide histone modification profiles for subsets of T cells isolated from peripheral blood of healthy and asthmatic individuals, we identified enhancers with known and potential roles in the normal differentiation of human TH1 cells and TH2 cells. We discovered disease-specific enhancers in T cells that differ between healthy and asthmatic individuals. Enhancers that gained the histone H3 Lys4 dimethyl (H3K4me2) mark during TH2 cell development showed the highest enrichment for asthma-associated single nucleotide polymorphisms (SNPs), which supported a pathogenic role for TH2 cells in asthma. In silico analysis of cell-specific enhancers revealed transcription factors, microRNAs and genes potentially linked to human TH2 cell differentiation. Our results establish the feasibility and utility of enhancer profiling in well-defined populations of specialized cell types involved in disease pathogenesis.

Adolescent↗

PubMedDate not supplied

Use of concanavalin A to analyse the mechanism of memory cell differentiation into killer cells.

The renewing by ConA of the cytolytic activity evaluated in a short-term chromium release assay in a population of memory cells obtained in a long-term mixed lymphocyte culture is shown to be largely dependent upon the dose of ConA used; a three staged phenomenon in terms of dose response and kinetics is analysed and suggests that at least for low concentration of ConA (0.5 micrograms/ml) the lectin acts on the same subpopulation and through the same mechanism as the specific antigen, as shown by DNA-synthesis inhibition experiments. Preincubation with ConA at doses giving the best secondary-like response strongly inhibits further response to the primary alloantigen. Experiments using mixtures of ConA and alloantigens as stimulators show that both agents can compete in differentiating memory cells into killer cells. All these data suggest an important overlap of the structures on memory cells which are triggered by ConA or specific antigen.

Animals↗

PubMed1978

Optimal strategies in immunology. II. B memory cell production.

After a first encounter with most antigens, the immune system responds to susequent encounters with a faster, more efficient and more strenuous antibody response. The memory of previous antigen contacts is carried by lymphocytes. Expanding on the model developed in Part 1 of this paper, we examine the optimal strategy available to the immune system for B memory cell production. We again find that the strategy should be of the bang-bang variety. The model we consider assumes that antigen triggers a subpopulation of B-lymphocytes. These triggered lymphocytes can proliferate and secrete modest amounts of antibody, or differentiate into non-dividing plasma cells which secrete large amounts of antibody, or differentiate into non-antibody secreting memory cells. Given injections of antigen at two widely spaced times we compute the strategy which minimizes a linear combination of the primary and secondary response times. We find that for all biologically reasonable parameter values the best strategies are ones in which memory cells are produced at the end of the primary response. Exerimental results which bear on the actual strategies employed are discussed.

Antibody Formation↗

PubMed1992

Helper T cell memory: more questions than answers.

The critical participation of helper T cells in immunologic memory of animals is clear. Features of antigen-specific CD4 memory cells in primed animals that distinguish them from naive cells are their increased frequency, their ability to secrete lymphokines in addition to IL-2 and their expression of distinct arrays of surface molecules. The latter include increased CD44, CD45RO, LFA-3 and VLA-4 and decreased CD45RA,B and Mel-14. These differences in surface markers may contribute to increased interaction potential for APC, and to distinct patterns of recirculation, but direct demonstrations of the former have yet to be provided. Other possible distinctions that are also largely hypothetical, include distinct requirements for activation and the ability to respond more rapidly to stimulation. The factors that regulate the development of memory helper T cells are also unknown.

Animals↗

PubMed1978

The cellular basis of allograft rejection in vivo. II. The nature of memory cells mediating second set heart graft rejection.

An adoptive transfer system was used to study the cellular basis of memory in animals immunized by grafting with major histocompatibility complex incompatible tissue. Memory was characterised by a large (greater than 100 fold) increase in the potency of lymphocytes to precure graft rejection. This increase in potency endured for at least 1 yr after sensitization. The memory cells were shown to be Ig-- small lymphocytes which were long lived and which did not recirculate from blood to lymph in normal recipients although they did home to lymphoid tissue from which they could be recovered several months later. The thymus was not required either for the generation of memory cells or their maintenance. Cells carrying memory for alloantibody synthesis did recirculate normally but alloantibody synthesis was shown not to be required for rejection.

Animals↗

PubMedDate not supplied

Regional accumulation of Pgp-1+ memory cells in senescent mucosal immune system.

The proportion of memory cells expressing the Pgp-1 surface marker, and subsets of T cells expressing L3T4 (CD4+ helper cells), Lyt-2 (CD8+ suppressor/cytotoxic cells), LFA-1 (lymphocyte function-associated antigen-1), and interleukin-2 receptors (IL-2R) on the cell surface in the spleen, regional lymph nodes (PLN), mesenteric LN (MLN), bronchial or mediastinal LN (BLN), Peyer's patches (PP), thymus, and bone marrow (BM) was studied in C57BL/6J mice of varying ages. Monoclonal antibodies (Mabs) IM7.8.1, FD4, GK1.5, 3.155, and FD441.8 were used to measure Pgp-1, IL-2R, L3T4 Lyt-2, and LFA-1 expressions, respectively. Optimal dose and kinetic studies were determined. The percentages of positive cells were determined by monoclonal antibody staining and flow cytometry or immunofluorescence microscopy. Using flow cytometric analysis, we found significant age-associated increases in the percentages of Pgp-1+ cells in the MLN as compared with a slight, but not significant, increase in the spleen. There were significant age-related increases in the percentages of Lyt-2+ cells in the spleen with no change in the MLN. The percentages of cells with the other phenotypic markers, L3T4, LFA-1, and IL-2R did not change with age in the spleen or MLN. Using immunofluorescence microscopy, the percentages of Thy-1.2+, Lyt-1+, and Lyt-2+ cells in different anatomical immune tissues did not change with age, except in the BLN and PP where there were significant age-related declines of the percentages of Thy-1.2+ and Lyt-2+ cells in the BLN, and of Lyt-1+ cells in the PP. These results indicate elevated levels of Pgp-1+ memory senescent cells in the MLN and these age-related shifts or changes in T lymphocyte subsets with age could contribute to the conserved immune responsiveness of senescent mucosal T lymphocytes.

Aging↗

PubMed1992

Specific epitope-induced conversion of CD8+ memory cells into effector cytotoxic T lymphocytes in vitro: presentation of peptide antigen by CD8+ T cells.

The requirements for the conversion of CD8+ memory T cells into effector class I major histocompatibility complex (MHC) Kd-restricted cytotoxic T (Tc) cells in vitro have been studied. Purified CD8+ splenocytes from influenza A/WSN-primed BALB/c (H-2d) mice stimulated with a synthetic nucleoprotein peptide 147-158 R156- (NPP) alone generated Tc cells specific for influenza virus-infected target cells. No additional requirements for accessory cells or their lymphokine products were necessary indicating that peptide antigen (Ag) in association with Kd was presented on CD8+ T cells. The evidence for presentation of NPP by CD8+ T cells was supported by the use of CD8+ memory T cells from semiallogeneic bone marrow radiation chimeras of P1----F1 type (H-2b----[H-2d x H-2b]F1). Memory CD8+ splenocytes from A/WSN-immune chimeras did not develop into secondary effector Tc cells as a result of a 4-day culture with NPP alone, however, were able to do so if NPP was presented by Kd-bearing Ag-presenting cells. In addition, these results exclude the possibility of direct recognition of free NPP molecules by the specific T cell receptor of CD8+ memory T cells. CD8+ memory splenocytes (H-2b) from chimeras were also able to develop into functionally active Tc cells as a result of presentation of Db-restricted synthetic peptide (NP 366-374) with a sequence derived from influenza virus nucleoprotein with high affinity for Db MHC class I molecules. Blockade of endogenously produced interleukin 2 (IL-2) activity by anti-IL-2 or anti-IL-2 receptor monoclonal antibody in the culture of CD8+ memory T cells during a 4-day NPP stimulation completely abolished Tc cell generation, indicating that the utilization of this lymphokine is absolutely required for the secondary Tc cell development. These findings demonstrate that CD8+ memory T cells per se are able to recognize the restimulating epitope as a result of its presentation by CD8+ T cells and develop into cytolytically active and highly specific Tc cells with no requirements for other cellular helper components or their lymphokine products.

Amino Acid Sequence↗

PubMed1976

T cell memory for the cytotoxic response to hapten-modified target cells.

This study describes the development of memory and cytotoxic murine T cells against syngeneic haptne N equals[N-(3-nitro-4-hydroxy-5-iodophenyl-acetyl)-Beta-alanylglycylglycyl] associated antigen. Memory activity in this system had the following characteristics. a) In vitro challenged cells primed in vivo resulted in an augmented cytotoxic response compared to cells primed in vitro. b) The augmented cytotoxic response in vitro was antigen-specific for both target cells in the lytic reaction and stimulator cells in the secondary response. c) Memory activity was long lasting (at least 2 months). d) Memory cells were not cytotoxic. e) Memory activity as well as the cytotoxic cells generated in a secondary response in vitro were T cell dependent, These findings are consistent with the results of others who have investigated T cell dependent memory in other cell-mediated reactions.

Animals↗

PubMed2025

Malonate promotes CD8+ T cell memory formation via protein malonylation.

Protein malonylation represents a recently identified posttranslational modification whose role in CD8+ T cell differentiation and functionality remains incompletely understood. In this study, we demonstrate that enhancing protein malonylation through sodium malonate (SM) treatment promotes CD8+ T cell memory formation in response to bacterial infection, subsequently potentiating recall responses. Comparative metabolomic analysis between SM-treated and control CD8+ T cells revealed significant metabolic alterations associated with protein malonylation. We present the first comprehensive proteomic analysis of lysine malonylation in murine CD8+ T cells, identifying 77 malonylation sites across 64 proteins involved in diverse cellular processes, particularly metabolic pathways. Malonylation of STAT6 was confirmed via the use of a specific chemical probe. Notably, we established that malonylation at the lysine 374 site of STAT6 results in increased TCF1 expression, due to alleviated transcriptional repression of TCF1 by STAT6. Collectively, our findings provide compelling evidence that protein malonylation plays a significant role in regulating CD8+ T cell memory formation.

Animals↗

PubMed1977

Feedback inhibition of IgM memory cells by high antigen dose.

The ability of high and low antigen doses (SRBC) to recruit IgM memory cells has been compared in several strains of mice. In intact animals priming with low doses was more efficient than priming with high doses. If, however, mice of different strains were X-irradiated two days after priming and repopulated, regardless of whether syngeneic or allogeneic splenocytes were used, they fell into two categories--those in which more memory cells were found after low antigen priming and those in which the reverse was true (Swiss mice). Two possible explanations are offered to explain these interstrain differences--antibody mediated suppression, and generation of suppressor T cells. Our data favor the latter, and we assume that suppressor T cells appear at different intervals after priming in different strains of mice, and that these cells are radioresistant.

Animals↗

PubMed1992

X-chromosome inactivation and cell memory.

Mammalian X-chromosome inactivation is an excellent example of the faithful maintenance of a determined chromosomal state. As such, it may provide insight into the mechanisms for cell memory, defined as the faithful maintenance of a determined state in clonally derived progeny cells. We review here the aspects of X-chromosome inactivation that are relevant to cell memory and discuss the various molecular mechanisms that have been proposed to explain its occurrence, with emphasis on DNA methylation and a recently proposed mechanism that depends on the timing of replication.

Animals↗

PubMed1975

Characteristics of immunological memory in mice. II. Resistance of nonrecirculating memory cells to antigen-mediated suppression of the secondary antibody response.

Mice were primed and subsequently challenged at various times with subcutaneous injections of sheep erythrocytes, and some characteristics of the secondary responses in the draining brachial and axillary lymph nodes were investigated. It was found that the secondary response within primed nodes was resistant to immunological preemption, a competition-like phenomenon which severely depresses primary responses. Since it was also shown that circulating memory cells could be inhibited by preempting injections of antigen, it was concluded that the resistance of primed nodes to preemption was due to the presence within them of a nonrecirculating subpopulation of memory cells. The size of this population was dependent both on the amount of priming antigen and the time after priming. The observation that the response given by these cells remained unaffected by doses of antigen which could depress a primary response does not favor the view that suppression of immune responses by preemption or antigenic competition is due to a factor which acts directly and indiscriminately on all immunologically competent cells.

Animals↗

PubMed1976

The role of B-cell memory in secondary IgG and IgM responses.

Mice were primed with the hapten 3-nitro-4-hydroxy-5 iodophenacetic acid (NIP) conjugated to chicken globulin (cg) and were boosted 2, 6, or 12 months later with CG conjugates of the related haptens 3,5-diiodo-4-hydroxyphenacetic acid (DIP) or 3-nitro-4-hydroxphenacetic acid (NP). Accelerated secondary responses were demonstrated both in the 7S and 19S class. Fine-specificities of secondary-response antibodies were studied by the hapten inhibition method of haptenated bacteriophage inactivation. 7S antibodies were found to have the fine-specificity of anti-NIP antibodies regardless of whether DIP or NP was the booster hapten ('original antigenic sin'). 19S antibodies had the fine-specificity of anti-DIP when DIP was the booster hapten. NP as the booster hapten resulted in 19S antibodies whose fine-specificity was intermediate between anti-NIP and anti-NP. A strong B-cell memory could thus be demonstrated in the 7S antibody response and a weak B-cell memory in the 19S antibody response.

Animals↗

PubMed1979

Functional depletion of T- and B-memory cells and other lymphoid cell subpopulations-during trypanosomiasis.

T. brucei infection in mice causes generalized immunosuppression with multiple changes in the cells of the lymphoid tissue. Loss of B cell responsiveness to antigens and mitogens, and the induction of suppressive T-cells and macrophages, have been previously reported (Hudson, Byner, Freeman & Terry, 1976; Corsini, Clayton, Askonas & Ogilvie, 1977; Jayawardena & Waksman, 1977). In this study, purified B- or T-cell populations from infected mice have been tested functionally in vitro or in vivo by transfer into syngeneic irradiated hosts to separate the cells from trypanosomes or their products. B-memory cells for thymus dependent (DNP-KLH) and thymus independent (DNP-Ficoll) antigens are depleted or lose their potential to respond to the antigen during T. brucei infection. Similarly, purified T-helper cells, and T-cells reactive to allogeneic target cells in mixed lymphocyte reactions are functionally defective. By 16 days of infection all these responses are less than 10% of the normal level. The loss of B-cell function follows the peak parasitaemia and is accompanied by increases in the serum levels of both IgM and IgG. Enhanced Ig production and decline in B-cell potential also occur in T-deprived mice and in CBA/N mice which lack a subset of T-independent B-cells. Cells affecting delayed hypersensitivity reactions retain their activity throughout trypanosome infection and so far provide the only exception to the general decline in immune potential.

Animals↗

PubMed1978

Role of membrane receptors in the induction of an in vitro secondary anti-hapten response. I. differentiation of B memory cells to plasma cells is independent of antigen-immunoglobulin receptor interaction.

In these experiments, we show that the interaction of antigen and B cell surface immunoglobulin is not essential for the generation of an IgG in vitro response to the hapten p-azophenyl-lactoside (lac). In our experimental system, keyhole limpet hemocyanin (KLH) was first selectively attached either to H-2, Ia or Ig receptors of lac-primed B cells by a hapten sandwich technique or to Fc receptors by complexes of azophenyl arsonate (ars)-coupled KLH and anti-ars. The labeled cells were then cultured with KLH-specific T cells for 5 days in the absence of antigen. Under all conditions of attachment we observed a significant anti-lac IgG response. We have demonstrated an absolute requirement for KLH-specific helper T cells. The results thus indicate that T helper cells are by themselves, regardless of the B cell antigen that serves to effect bridging, sufficient to activate B memory cells. We could find no evidence to support either a matrix theory or a two-signal hypothesis as currently proposed.

Animals↗

PubMed1978

Role of membrane receptors in the induction of an in vitro secondary anti-hapten response. II. Antigen-immunoglobulin receptor interaction is not required for B memory cell proliferation.

In this study it has been investigated whether the interaction of antigen and B cell surface immunoglobulin (sIg) is required for full clonal expansion of memory B cells specific for the hapten, p-azophenyl-lactoside (lac). Cultures of lac-primed B cells and keyhole limpet hemocyanin (KLH)-specific T cells were activated in three ways: (a) by the antigen lac-KLH, (b) in the absence of lac epitopes by attaching KLH to the H-2 antigens of the B cells, and (c) in similar conditions where lac epitopes were supplied on carriers unrecognized by helper T cells. Dilution analyses showed that the yield of IgG anti-lac plaques per activated precursor was identical in all situations, and that the increased responses observed in the presence of lac epitopes were due to an increase in the frequency of activated precursors. Our results thus indicate that specific interacting T cells convey both the differentiative and proliferative signals to B memory cells, and are at variance with proposals advocating that an antigen-induced proliferative phase is succeeded by a T-cell-dependent differentiative event. We suggest that the effect of sIg-antigen interaction may be to cycle some precursors into a more easily activated state.

Animals↗