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Results for “Memory T Cells”

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PubMed2001

CD4(+) T cell effectors can become memory cells with high efficiency and without further division.

Whether memory T lymphocytes are derived directly from effector T cells or via a separately controlled pathway has long been debated. Here we present evidence that, after adoptive transfer, a large fraction of in vitro--derived effector CD4(+) T cells have the potential to become memory T cells and that this transition can occur without further division. This data supports a linear pathway from effector to memory cells and suggests that most properties of memory cells are predetermined during effector generation. We suggest, therefore, that evaluation of vaccine efficacy in the induction of memory CD4(+) T cells should focus on the effector stage.

Animals↗

PubMed2003

Interleukin 7 and T cell receptor signals regulate homeostasis of CD4 memory cells.

Immunological memory depends on the long-term maintenance of memory T cells. Although the factors that maintain CD8 T cell memory are well understood, those responsible for CD4 memory are not well defined. We have shown here that interleukin 7 (IL-7) was an important survival factor for CD4 memory T cells that together with T cell receptor (TCR) signals regulated homeostasis of the CD4 memory population in lymphopenic conditions and in the intact immune system. Thus, IL-7 contributes to the maintenance of all naive and memory T cell subsets, and therefore controls the overall size of the T cell pool.

Animals↗

PubMed2006

Mathematically modeling dynamics of T cell responses: predictions concerning the generation of memory cells.

Mathematical models of T cell population dynamics after infection typically assume that T cells differentiate according to a linear process in which they first become effector cells, and then after some time, differentiate further into memory cells. In this paper, we offer a different mathematical model which can equally well capture T cell dynamics, using data from lymphocytic choriomeningitis (LCMV) infection. Our model assumes that memory cells are intermediates that further differentiate into effector cells only from additional or stronger antigenic stimulation. Our assumption naturally leads to a testable prediction about the generation of T cell memory-that the memory phenotype of T cells should be present in detectable numbers during the expansion phase of the response. We use our model to estimate a rate of differentiation from memory type cells to effectors. We argue that this differentiation assumption, where memory cells are intermediates, captures recent experimental work on T cell differentiation, and hence this new mathematical model could be helpful in doing further studies of T cell population dynamics. We also propose a method of distinguishing the models by examining the ratio of memory T cells detectable long after an infection to the peak numbers of T cells at the end of the expansion phase.

CD4-Positive T-Lymphocytes↗

PubMed1990

Maintenance of B-cell memory by long-lived cells generated from proliferating precursors.

A basic feature of T-cell dependent antibody responses is the generation of memory: on a second contact with an antigen a secondary response is produced in which somatically mutated antibodies with increased affinity are synthesized. Memory can persist for long periods of time. This has classically been ascribed to the generation of long-lived memory B cells. However, it is also possible that persisting antigen, on which memory may depend, maintains a population of cycling memory cells under continuous selection or continuously recruits newly generated B cells into the memory B-cell compartment. To discriminate between these mechanisms we have now directly analysed the proliferative activity in the memory B-cell compartment of the mouse by measuring bromodeoxyuridine incorporation in vivo. We show that after an initial phase of extensive proliferation after primary immunization, memory cells can persist in the organism for extended periods of time in the absence of cell division.

Animals↗

PubMed1998

Long-term T cell memory requires the surface expression of self-peptide/major histocompatibility complex molecules.

How memory T cells are maintained in vivo is poorly understood. To address this problem, a male-specific peptide (H-Y) was identified and used to activate female anti-H-Y T cells in vitro. Anti-H-Y T cells survived in vivo for at least 70 days in the absence of antigen. This persistence was not because of the intrinsic ability of memory T cells to survive in vivo. Instead, the survival and function of adoptively transferred memory cells was found to require transporter of antigen protein 1-dependent expression of self-peptide/major histocompatibility complex class I molecules in recipient animals. Therefore, it appears that the level of T cell receptor engagement provided by transporter of antigen protein 1-dependent, self-peptide/major histocompatibility complexes is sufficient to maintain the long-term survival and functional phenotype of memory cells in the absence of persistent antigen. These data suggest that positive selection plays a role not only in T cell development but also in the maintenance of T cell memory.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2006

Bim mediates apoptosis of CD127(lo) effector T cells and limits T cell memory.

Following an acute T cell response, most activated effector cells die, while some survive and become memory cells. The pro-apoptotic Bcl-2 family member, Bcl-2 interacting mediator of death (Bim) is critical for eliminating most effector T cells, while expression of CD127 (IL-7Ralpha) has been proposed to mark effector cells destined to become memory cells. Here, we examined the effects of Bim on the death of effector T cells in relationship to CD127 expression and on development of T cell memory following lymphocytic choriomeningitis virus (LCMV) infection. We found that large numbers of CD127(lo) LCMV-specific CD4(+) and CD8(+) T cells were lost in wild-type mice, but were spared in Bim(-/-) mice. Further, while the numbers of CD127(hi) T cells declined only slightly during contraction of the response in wild-type mice, they increased significantly in Bim(-/-) mice due to re-expression of CD127 on CD127(lo) T cells that had avoided apoptosis. Functional memory T cells were significantly increased in Bim(-/-) mice; however, they underwent a slow attrition due to decreased proliferative renewal. Taken together, these data suggest that the absence of Bim-mediated death of LCMV-specific CD4(+) and CD8(+) T cells in vivo can increase T cell memory, but other homeostatic mechanisms control the long-term maintenance of memory cells.

Animals↗

PubMed1999

Human virus-specific CD8+ CTL clones revert from CD45ROhigh to CD45RAhigh in vivo: CD45RAhighCD8+ T cells comprise both naive and memory cells.

It has been generally believed that human CD8+ memory cells are principally found within the CD45ROhigh population. There are high frequencies of CD8+ memory CTL specific for the human CMV tegument phosphoprotein pp65 in PBMC of long-term virus carriers; the large population of memory CTL specific for a given pp65 peptide contains individual CTL clones that have greatly expanded. In this study, we found high frequencies of pp65 peptide-specific memory CTL precursors in the CD45ROhighCD45RA- population, but also appreciable frequencies in the CD45RAhigh subpopulation. Because the majority of CD8+ T cells in PBMC are CD45RAhigh, more of the total pp65-specific memory CTL pool is within the CD45RAhigh than in the CD45ROhigh compartment. Using clonotypic oligonucleotide probes to quantify the size of individual pp65-specific CTL clones in vivo, we found the CD45RAhigh population contributed 6- to 10-fold more than the CD45ROhigh population to the total virus-specific clone size in CD8+ cells. During primary CMV infection, an individual virus-specific CTL clone was initially CD45ROhigh, but after resolution of infection this clone was detected in both the CD45ROhigh and the CD45RAhigh populations. We conclude that CD45RA+ human CD8+ T cells do not solely comprise naive cells, but contain a very significant proportion of memory cells, which can revert from the CD45ROhigh to CD45RAhigh phenotype in vivo.

Carrier State↗

PubMed2004

Apoptosis and loss of virus-specific CD8+ T-cell memory.

CD8(+) T-cell memory to viruses is stable in the absence but volatile in the presence of other infections. Apoptotic events that occur early in acute infections delete pre-existing memory T cells, leaving the host with reduced memory (except for cross-reactive responses) to previously encountered viruses. Apoptotic events also silence the acute immune response, leaving the host with a residual population of memory T cells. Persistent infections can induce apoptotic deletions of memory T cells that are specific to the persisting virus and to previously encountered pathogens.

Animals↗

PubMed2003

Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells.

A major unanswered question is what distinguishes the majority of activated CD8 T cells that die after an acute viral infection from the small fraction (5-10%) that survive to become long-lived memory cells. In this study we show that increased expression of the interleukin 7 receptor alpha-chain (IL-7Ralpha) identifies the effector CD8 T cells that will differentiate into memory cells. IL-7R(hi) effector cells contained increased amounts of antiapoptotic molecules, and adoptive transfer of IL-7R(hi) and IL-7R(lo) effector cells showed that IL-7R(hi) cells preferentially gave rise to memory cells that could persist and confer protective immunity. Thus, selective expression of IL-7R identifies memory cell precursors, and this marker may be useful in predicting the number of memory T cells generated after infection or immunization.

Adoptive Transfer↗

PubMed2007

B and T lymphocyte attenuator regulates CD8+ T cell-intrinsic homeostasis and memory cell generation.

B and T lymphocyte attenuator (BTLA) is a negative regulator of T cell activation, but its function in vivo is not well characterized. Here we show that mice deficient in full-length BTLA or its ligand, herpesvirus entry mediator, had increased number of memory CD8(+) T cells. The memory CD8(+) T cell phenotype resulted from a T cell-intrinsic perturbation of the CD8(+) T cell pool. Naive BTLA-deficient CD8(+) T cells were more efficient than wild-type cells at generating memory in a competitive antigen-specific system. This effect was independent of the initial expansion of the responding antigen-specific T cell population. In addition, BTLA negatively regulated antigen-independent homeostatic expansion of CD4(+) and CD8(+) T cells. These results emphasize two central functions of BTLA in limiting T cell activity in vivo.

Animals↗

PubMed1969

Cell separation on antigen-coated columns. Elimination of high rate antibody-forming cells and immunological memory cells.

Glass and plastic bead columns coated with antigenic protein molecules were used as an immunological filter for cell populations containing immune cells of relevant specificity. A selective elimination of these immune cells from the passing cell suspension was regularly noted and it approached, in some experiments, complete abolition of the specific immune reactivity of the filtered cell population. This specific retention of immune cells by antigenic columns could be selectively blocked by the presence of free antigen molecules in the medium during filtration. The results obtained support the concept of a cell-associated antigen-specific receptor being present on the outer surface of immune cells, displaying the same antigen-binding specificity as the potential product of the cell, the humoral antibody. Using the present bead column system, results were obtained indicating that this receptor was an active product of the immune cells and not any passively adsorbed, cytophilic antibody. Antigenic bead columns may very well constitute a tool for the production in vitro of cell populations being specifically deprived of immune reactivity and allow detailed analysis of the characteristics of the cell-associated antibody of immune cells.

Animals↗

PubMed2000

High density insulin receptor-positive diabetogenic T lymphocytes in nonobese diabetic mice are memory cells.

Our previous work examining the importance of insulin receptor (IR) expression on T cells has demonstrated that when T cells from nonobese diabetic mice were sorted into populations expressing a high (IR(High)) and a low (IR(Low)) density of IR, IR(High) T cells rapidly transferred insulitis and diabetes. We have further characterized IR(High) T cells. Both CD4+ and CD8+ cells were detected in the IR(High) T cell population, but IR(High) expression was detected predominantly on CD4+ cells. IRHigh T cells were polyclonal for TCR Vbeta-chain expression. By 3 color flow cytometric analysis, virtually all IR(High) T cells expressed low or negligible levels of CD62L (CD62L(Low)/-) and high levels of CD44 (CD44(High)). The lack of IL-2 receptor and transferrin receptor expression as seen previously, together with the CD62L(Low)/- CD44(High) phenotype suggests that IR(High) T cells are memory cells. However, since only about one quarter of all of the CD62L(Low)/- or CD44(High) T cells were also IR(High), the IR(High) phenotype defines a subpopulation of memory T cells that are aggressively diabetogenic.

Animals↗

PubMed1995

Human recombinant IL-4 decreases the emergence of non-specific cytolytic cells and favours the appearance of memory cells (CD4+CD45RO+) in the IL-2-driven development of cytotoxic T lymphocytes against autologous ovarian tumour cells.

As IL-4 and IL-6 have also been reported to promote the development of T lymphocytes such as IL-2, we investigated their role in the development of specific cytotoxic T lymphocytes (CTL) against autologous ovarian tumours in mixed lymphocyte tumour cultures (MLTC). Peripheral blood lymphocytes (PBL) from five ovarian carcinoma (OC) patients were incubated with autologous OC cells at a PBL:OC cell ratio of 20:1 in IL-2 alone (50 U/ml for the first week and 200 U/ml thereafter) or with IL-4 (100 U/ml) and/or IL-6 (5 U/ml). Neither IL-4 nor IL-6 improved lymphocyte proliferation consistently. In contrast, IL-4 reduced significantly the development of LAK activity as assayed against Daudi cell line, and decreased modestly the emergence of natural killer (NK) activity as assayed against K562. This property was not shared by IL-6. The prevention of the development of non-specific cytolytic activity (LAK and NK activities) was much stronger when the MLTC was started with IL-4 in the absence of IL-2 during the first week in culture. A concomitant drop in NKH-1 expression (CD56) was observed. By inhibiting the emergence of non-specific cytotoxicity, IL-4 provided better evidence of the specific cytolytic activity directed at ovarian cells. In parallel, a significant increase in the generation of memory cells (CD4+CD45RO+) was observed with IL-4. In conclusion, in this model, IL-4 added before IL-2 decreases significantly the emergence of non-specific cytotoxic cells, and promotes the generation of memory cells. These properties may be of interest in the design of strategies aimed at obtaining tumour-specific cells for investigational and immunotherapeutic purposes.

CD4 Antigens↗

PubMed2005

B cell memory to 3 Plasmodium falciparum blood-stage antigens in a malaria-endemic area.

To gain insight into why antibody responses to malarial antigens tend to be short lived, we studied antigen-specific memory B cells from donors in an area where malaria is endemic. We compared antibody and memory B cell responses to tetanus toxoid with those to 3 Plasmodium falciparum candidate vaccine antigens: the C-terminal portion of merozoite surface protein 1 (MSP1(19)), apical membrane antigen 1 (AMA1), and the cysteine-rich interdomain region 1 alpha (CIDR1 alpha ) of a protein from the P. falciparum erythrocyte membrane protein 1 (PfEMP1) family. These data are the first to be generated on memory B cells in children who are in the process of acquiring antimalarial immunity, and they reveal defects in B cell memory to P. falciparum antigens. Compared with the results for tetanus toxoid, more donors who were positive for antibody to AMA1 and CIDR1 alpha were negative for memory B cells. These data imply that some exposures to malaria do not result in the establishment of stable populations of circulating antigen-specific memory B cells, suggesting possible mechanisms for the short-lived nature of many anti-malarial antibody responses.

Adult↗

PubMed2004

CD4 T-cell memory.

CD4 T-cell memory is in some ways more enigmatic than CD8 T-cell memory. This is mostly due to the fact that CD4 T cells tend to expand far less in response to antigenic stimuli, thereby thwarting attempts at their detection during the course of an immune response. Nevertheless, there is a wide range of experimental models that have provided information regarding the survival and maintenance of CD4 memory cells, their functional capacities, their differentiation states and program of development following activation. The emerging picture is one of great versatility and functional heterogeneity as befits their central position within the immune system.

Animals↗

PubMed2003

Increased CD8+ T cell memory to concurrent infection at the expense of increased erosion of pre-existing memory: the paradoxical role of IL-15.

The use of cytokines during vaccination, particularly IL-15, is being considered due to the unique ability of IL-15 to enhance the proliferation of memory CD8(+) T cells. However, as homeostatic mechanisms limit excessive lymphocyte expansion, we addressed the consequences of this enhancement of T cell memory by IL-15. Infection of mice with either recombinant Mycobacterium bovis (BCG) expressing IL-15 (BCG-IL-15) or BCG and purified IL-15 resulted in an increased CD44, IL-2Rbeta expression and increased frequency of IFN-gamma-secreting CD8(+) T cells. Surprisingly, the enhancement of memory to concurrent infection by IL-15 exacerbated the attrition of pre-existing memory. Infection of mice with Listeria monocytogenes expressing OVA resulted in potent OVA(257-264)-specific CD8(+) T cell memory, and a challenge of these mice with either BCG-IL-15 or BCG and purified IL-15 resulted in an increased erosion of OVA(257-264)-specific CD8(+) T cell memory, relative to BCG. Enhancement in the erosion of OVA-specific CD8(+) T cell memory by BCG-IL-15 resulted in a consequently greater impairment in protection against a challenge with OVA-expressing tumor cells. We thus raise important questions regarding vaccinations that are aimed at maximizing T cell memory without considering the impact on pre-existing T cell memory.

Adjuvants, Immunologic↗

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↗

PubMed1993

A possible role for bcl-2 in regulating T-cell memory--a 'balancing act' between cell death and survival.

One of the central questions in T-cell immunity is how the generation of T-cell memory may proceed simultaneously with the maintenance of T-cell homeostasis. In this article, we present a hypothesis that the regulation of bcl-2 gene expression within the activated CD45RO+ T-cell population may be one of the key factors in the balance between death and survival of these activated mature T cells, both in vitro and in vivo.

Animals↗