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Results for “Memory T Cells”

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PubMed2006

B-cell memory: are subsets necessary?

B-cell memory is provided by populations of quiescent memory B cells and long-lived plasma cells. Whereas it is clear that both of these cell populations arise from germinal centres, the signals and circumstances that trigger germinal-centre B cells to enter and then persist in memory compartments are poorly defined. Here, I propose that germinal centres produce memory B cells and plasma cells throughout the immune response and that memory B cells arise by the emigration of B cells that are chosen at random from the pool available in the germinal centre. The ability of such emigrants to survive as memory B cells depends on their germinal-centre 'history', with the persistence of high-affinity B-cell variants being favoured.

Animals↗

PubMed2000

Antiviral B cell memory in the absence of mature follicular dendritic cell networks and classical germinal centers in TNFR1-/- mice.

TNFR1-/- mice have been shown to lack networks of mature follicular dendritic cells (FDCs) and they do not form germinal centers. With nonreplicating Ags, IgG titers were inefficiently induced and not maintained. In this study, the neutralizing Ab response and the establishment of B cell memory in TNFR1-/- mice after infection with vesicular stomatitis virus (VSV) were analyzed histologically and functionally. Immunization with VSV-derived protein Ags without adjuvant induced only IgM but no IgG Abs in TNFR1-/- mice, whereas VSV glycoprotein emulsified in CFA or IFA induced IgM and IgG responses that were short-lived and of moderate titer. However, infection with live VSV induced excellent neutralizing IgM and IgG responses in TNFR1-/- mice, and adoptively transferable B cell memory was generated and persisted for more than 300 days. In contrast, IgG levels and Ab-forming cells in the bone marrow declined within 300 days by 90-95% compared with controls. These findings suggest that 1) increased Ag dose and time of Ag availability can substitute for FDC-stored Ab-complexed Ag in the induction of efficient IgG responses in TNFR1-/- mice devoid of classical germinal centers; 2) the induction and maintenance of adoptively transferable B cell memory can occur in the absence of Ag bound to mature FDCs; and 3) the long-term maintenance of elevated IgG titers is largely dependent on FDC-associated persisting Ag. However, about 5-10% of the Ab production remained in the absence of detectable persisting Ag in TNFR1-/- mice, probably either due to immature FDCs being partially functional and/or due to long-lived plasma cells.

Adoptive Transfer↗

PubMed1983

Relationship of germinal centers in lymphoid tissue to immunologic memory. VI. Transfer of B cell memory with lymph node cells fractionated according to their receptors for peanut agglutinin.

We isolated germinal center B cells by exploiting their high affinity for peanut agglutinin (PNA). The PNA+ and PNA- B cells, fractionated by panning on PNA-coated petri dishes, were examined for their ability to transfer memory responses to irradiated recipients at various times after priming. With such fractionated B cells from lymph nodes taken at the peak of germinal center formation, the largest response was obtained in recipients of the PNA+ B cell population. At 4 to 5 wk after priming, and 10 days after challenge with an unrelated antigen, memory responses were approximately equal in recipients of PNA+ or PNA- B cells. At 14 wk after priming, memory responses were found only in recipients of the PNA- B cell population. Memory B cells from the spleen, taken from mice primed in the footpad 8 wk earlier, were also PNA-. Finally, we show that boosting with a TNP-conjugate in the footpad, 6 mo after priming in the same footpad, induced the reappearance of marked memory responsiveness in the PNA+ B cell fraction of the draining node.

Animals↗

PubMed1980

T cell dependent and independent steps in IgE-B memory cell development.

The role of T cells in the IgE antibody response was studied using athymic nu/nu mice which failed to form IgE antibody against either T-dependent or T-independent antigens. Evidence was obtained that hapten-specific B cells can be primed with T-dependent or T-independent antigens in the absence of T cells. Transfer of nu/nu spleen cells primed with alum-absorbed dinitrophenyl (DNP) ovalbumin or DNP derivatives of Salmonella bacilli into irradiated nu/+ mice, together with unprimed T cells, enhanced IgE antihapten antibody response of the recipients to alum-absorbed DNP-KLH. The antigen-primed nu/nu spleen cells, however, did not contain hapten-specific B memory cells directly committed to IgE response, since no antihapten IgE antibody response was obtained when the same DNP-primed nu/nu spleen cells were transferred into irradiated mice, together with KHL-primed nu/+ spleen cells, and the recipients were challenged with DNP-KLH without adjuvant. Once IgE-B memory cells responded to DNP derivatives of both T-dependent and T-independent carriers to form a significant amount of antihapten IgE antibody without participation of T cells. The results indicate that the essential role of T helper cells in the IgE antibody response is in the process of the development of IgE-B memory cells.

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↗

PubMed1981

Immunological memory to Listeria monocytogenes in rodents. IV. Studies on origin and fate of tissue-positioned T memory cells.

In this report on memory T cells mediating anti-microbial resistance to Listeria monocytogenes (LM) it was analysed whether memory cells found in tissue during late-phase (e.g. 10-60 days after infection) are long-lived progeny of cells which settled in tissues during early phase (e.g. 4-10 days after infection), or whether they are short lived but constantly replaced from other sources of memory cells. The study provides evidence for both mechanisms. Transfer and parabiosis experiments as well as radiometric and autoradiographic studies suggested that early-phase cells give rise to late-phase memory cells in the extravascular compartment. These memory cells were shown to mediate resistance and respond to antigen in vitro. Mediators of resistance in the unstimulated peritoneal cavity during late-phase are long-lived. On the other hand, parabiosis studies suggested that late-phase resident peritoneal cells which mediate resistance and respond to antigen in vitro have in part arrived after the end of early phase. Such cells are found in low numbers in central lymph during late-phase. The simplest interpretation of these data is that LM-specific lymphoblasts spontaneously extravasate and settle in tissues as long-lived memory cells. Since the numbers of LM-specific lymphoblasts released from lymphoid tissue is highest during early phase, the majority of resident memory cells are progeny of early-phase lymphoblasts.

Animals↗

PubMed2006

Intestinal double-positive CD4+CD8+ T cells are highly activated memory cells with an increased capacity to produce cytokines.

Peripheral blood and intestinal CD4+CD8+ double-positive (DP) T cells have been described in several species including humans, but their function and immunophenotypic characteristics are still not clearly understood. Here we demonstrate that DP T cells are abundant in the intestinal lamina propria of normal rhesus macaques (Macaca mulatta). Moreover, DP T cells have a memory phenotype and are capable of producing different and/or higher levels of cytokines and chemokines in response to mitogen stimulation compared to CD4+ single-positive T cells. Intestinal DP T cells are also highly activated and have higher expression of CCR5, which makes them preferred targets for simian immunodeficiency virus/HIV infection. Increased levels of CD69, CD25 and HLA-DR, and lower CD62L expression were found on intestinal DP T cells populations compared to CD4+ single-positive T cells. Collectively, these findings demonstrate that intestinal and peripheral blood DP T cells are effector cells and may be important in regulating immune responses, which distinguishes them from the immature DP cells found in the thymus. Finally, these intestinal DP T cells may be important target cells for HIV infection and replication due to their activation, memory phenotype and high expression of CCR5.

Animals↗

PubMed1982

Plasma cells and their precursors. II. Kinetics of B-memory cell production in rabbits.

Rabbits were irradiated with 4.5 Gy in order to eliminate completely preexisting antibody-forming cell precursors. Sheep red blood cells were administered 24 h or 8 days after irradiation in order to induce the production of IgG B-memory AFCP. Resulting B-memory cells were triggered into antibody synthesis by a second dose of SRBC given 8 days after the challenge; the resulting IgG antibody clones were analyzed by isoelectric focusing. Memory IgG antibody clones were detectable from the third day after secondary immunization onward. It is concluded that antigen administered as early as 24 h after the irradiation induces B-memory cell production equally well as primary immunization 8 days after the irradiation. This B-memory cell production proceeds in the absence of detectable primary IgG antibody formation. Irradiated non-immunized rabbits showed spontaneous reappearance of IgG-AFCP with specificities to SRBC. In sharp contrast to the specifically induced production of B-memory IgG-AFCP mentioned above, this process took more than two months to reach potentialities comparable to those of "preexistent" AFCP present in normal, control rabbits.

Animals↗

PubMed2006

CD4+ T-cell memory: generation and multi-faceted roles for CD4+ T cells in protective immunity to influenza.

We have outlined the carefully orchestrated process of CD4+ T-cell differentiation from naïve to effector and from effector to memory cells with a focus on how these processes can be studied in vivo in responses to pathogen infection. We emphasize that the regulatory factors that determine the quality and quantity of the effector and memory cells generated include (i) the antigen dose during the initial T-cell interaction with antigen-presenting cells; (ii) the dose and duration of repeated interactions; and (iii) the milieu of inflammatory and growth cytokines that responding CD4+ T cells encounter. We suggest that heterogeneity in these regulatory factors leads to the generation of a spectrum of effectors with different functional attributes. Furthermore, we suggest that it is the presence of effectors at different stages along a pathway of progressive linear differentiation that leads to a related spectrum of memory cells. Our studies particularly highlight the multifaceted roles of CD4+ effector and memory T cells in protective responses to influenza infection and support the concept that efficient priming of CD4+ T cells that react to shared influenza proteins could contribute greatly to vaccine strategies for influenza.

Animals↗

PubMed2005

Regulation of CD4 T cell memory by OX40 (CD134).

CD4 memory T cells play a critical role in protection against repeated exposure to infectious agents such as viruses, bacteria, and helminth parasites, yet can also contribute to the aberrant immune responses associated with autoimmune and allergic reactions. Understanding the mechanisms that control effective memory responses has important ramifications for vaccine design and in the management of adverse immune reactions. Recent advances in studies of T cell memory have implicated the tumor-necrosis-factor receptor (TNFR) family member, OX40 (CD134), as a key co-stimulatory molecule involved in the regulation of CD4 memory T cells. In this review we discuss these new developments in the context of past research and current models for the generation, persistence, and re-activation of memory T cells.

Animals↗

PubMed2002

Development and homeostasis of T cell memory in rhesus macaque.

The rhesus macaque (RM) is a critical animal model for studies of viral pathogenesis and immunity, yet fundamental aspects of their cellular immune response remain poorly defined. One such deficiency is the lack of validated phenotypic signatures for their naive and memory T cell subsets, and the resultant unavailability of accurate information on their memory T cell development, homeostasis, and function. In this study, we report a phenotypic paradigm allowing definitive characterization of these subsets and their comprehensive functional analysis. Naive T cells are optimally delineated by their homogeneous CD95(low)CD28(high)beta(7) integrin(int) (CD4+) or CD95(low)CD28(int)CD11a(low) (CD8+) phenotypes. This subset 1) was present in blood and secondary lymph tissues, but not effector sites; 2) vastly predominated in the fetal/neonatal immune system, but rapidly diminished with postnatal age; 3) lacked IFN-gamma production capability, and specific responses to RM CMV; and 4) demonstrated low in vivo proliferative activity. CD4+ and CD8+ memory subsets were CD95(high), but otherwise phenotypically heterogeneous and included all IFN-gamma production, RM CMV-specific responses, effector site T cells, and demonstrated high in vivo proliferative activity ( approximately 10 times the naive subset). These analyses also revealed the RM "effector memory" subset within the overall memory population. This population, best defined by lack of CD28 expression, contained the majority of RM CMV-specific cells, was highly enriched in extralymphoid effector sites, and comprised an increasing proportion of total memory cells with age. The effector memory subset demonstrated similar in vivo proliferative activity and survival as CD28+ "central memory" T cells, consistent with independent homeostatic regulation.

Age Factors↗

PubMed2003

CD4+ cell memory: the enigma of Th1 cells.

Despite a wealth of information pertaining to functional and phenotypic attributes of memory CD4(+) cells, the mechanisms that underlie the generation and persistence of memory in this subset are largely unknown. Recent work suggests that the development of memory might be differently regulated in T-helper-1 and T-helper-2 cells, owing to differences in their susceptibility to cell death. These studies support a new paradigm, in which memory T cells are heterogeneous in terms of their stage of maturation and function as well as mechanisms of homeostatic control.

Animals↗

PubMed1992

Memory cell generation ablated by soluble protein antigen by means of effects on T- and B-lymphocyte compartments.

Adult C57BL/6 mice were injected with 100 micrograms of soluble, freshly deaggregated human serum albumin (HSA) to produce partial immunologic tolerance. Uninjected normal control (N) mice contain only approximately 100 B cells in their spleens with the capacity to (i) be activated in vitro into clonal proliferation by Escherichia coli lipopolysaccharide plus interleukins 2, 4, and 5, (ii) form IgG1 as well as IgM antibody, and (iii) display specificity for HSA when only IgG1 is allowed to score in an enzyme-linked immunosorbent assay (ELISA). Such N mice generate approximately 50,000 clonable anti-HSA IgG1 antibody-forming cell precursors in their spleens after T-dependent immunization with HSA absorbed onto alum and given with Bordetella pertussis adjuvant. Mice preinjected with soluble HSA (TOL) generate far fewer anti-HSA IgG1 antibody-forming cell precursors, termed anti-HSA memory cells. Splenocytes were transferred from N or TOL mice into lethally irradiated syngeneic recipients together with syngeneic bone marrow. Whereas N splenocytes generated plentiful memory cells within 2 weeks in antigenically challenged recipients, TOL splenocytes did not. Work with Ly-5 congenic mice ruled out memory cell generation from either the host or the bone marrow inoculum within this limited time. N T cells plus TOL B cells showed consistently lowered memory cell generation. TOL T cells plus N B cells showed an even greater lowering of adoptive memory cell generation. Thus the lowered response capacity of TOL mice resided in the T- and B-cell compartments. Attempts to show a suppressor component within the T-cell population were inconclusive, but a profound defect in capacity to respond to HSA in vitro was exhibited by the CD4+ T cells of TOL mice. B lymphocytes were harvested from T-dependently immunized mice 5 days after challenge, incubated with soluble HSA for 18 hr, and then adoptively transferred together with N T cells. The recently activated B cells were not rendered tolerant by this manipulation. The results argue for a major T-cell component in the process whereby soluble protein antigens ablate affinity maturation and memory cell generation.

Animals↗

PubMed1999

Functionally heterogeneous CD8(+) T-cell memory is induced by Sendai virus infection of mice.

It has recently been established that memory CD8(+) T cells induced by viral infection are maintained at unexpectedly high frequencies in the spleen. While it has been established that these memory cells are phenotypically heterogeneous, relatively little is known about the functional status of these cells. Here we investigated the proliferative potential of CD8(+) memory T cells induced by Sendai virus infection. High frequencies of CD8(+) T cells specific for both dominant and subdominant Sendai virus epitopes persisted for many weeks after primary infection, and these cells were heterogeneous with respect to CD62L expression (approximately 20% CD62L(hi) and 80% CD62L(lo)). Reactivation of these cells with the antigenic peptide in vitro induced strong proliferation of antigen-specific CD8(+) T cells. However, approximately 20% of the cells failed to proliferate in vitro in response to a cognate peptide but nevertheless differentiated into effector cells and acquired full cytotoxic potential. These cells also expressed high levels of CD62L (in marked contrast to the CD62L(lo) status of the proliferating cells in the culture). Direct isolation of CD62L(hi) and CD62L(lo) CD8(+) T cells from memory mice confirmed the correlation of this marker with proliferative potential. Taken together, these data demonstrate that Sendai virus infection induces high frequencies of memory CD8(+) T cells that are highly heterogeneous in terms of both their phenotype and their proliferative potential.

Animals↗

PubMed1996

Induction of antibody-secreting cells and T-helper and memory cells in murine nasal lymphoid tissue.

Intranasal (i.n.) immunization is an effective route for inducing mucosal immune responses especially in the upper respiratory tract and mouth. To characterize the cells involved in these responses, nasal lymphoid tissue (NALT; considered to be the equivalent of Waldeyer's ring in humans) of normal mice, and of mice immunized intranasally with a bacterial protein antigen conjugated to cholera toxin B subunit, was isolated and the lymphoid cells analysed according to surface phenotype, immunoglobulin and antibody secretion, and cytokine profile. Compared with cells obtained from Peyer's patches (PP), NALT cells contained a higher proportion of T cells, especially naive (CD45RB+hi) T-helper cells, and fewer surface (s)IgA+ cells. Both tissues contained high proportions of sIgM+ IgD+ unswitched B cells. After i.n. immunization, IgA antibody-secreting cells were increased, indicating that isotype switching and differentiation of B cells to IgA-secreting cells occurred in NALT, whereas smaller numbers of antibody-secreting cells were found in PP after intragastric (i.g.) immunization. Antigen-specific memory cells persisted in NALT for at least 8 months after initial immunization. The cytokine expression profiles of antigen-stimulated NALT and PP cells of immunized mice, revealed by reverse transcription polymerase chain reaction analysis of mRNA, were similar. Both NALT and PP cells tended to express type 2 earlier or for longer than type 1 cytokine mRNA, but NALT cells tended to express interleukin-4 (IL-4) earlier, and IL-5 for a longer period, than PP cells. Thus NALT shares with PP cell populations typical of a mucosal inductive site, including unswitched B cells and naive T-helper (Th) cells. After i.n. immunization, NALT has the capacity to provide help for B-cell maturation and differentiation, as well as to maintain immune memory.

Animals↗

PubMed2004

Plasticity of T cell memory responses to viruses.

Virus-specific memory T cell populations demonstrate plasticity in antigenic and functional phenotype, in recognition of antigen, and in their ability to accommodate new memory T cell populations. The adaptability of complex antigen-specific T cell repertoires allows the host to respond to a diverse array of pathogens and accommodate memory pools to many pathogens in a finite immune system. This is in part accounted for by crossreactive memory T cells, which can be employed in immune responses and mediate protective immunity or life-threatening immunopathology.

Animals↗

PubMed1987

Gut mucosal immunization with reovirus serotype 1/L stimulates virus-specific cytotoxic T cell precursors as well as IgA memory cells in Peyer's patches.

In this report we have shown that reovirus 1/L is an effective mucosal immunogen capable of generating a cytotoxic T cell (CTL) and associated helper T cell response to the nominal antigens associated with reovirus 1/L. The effectors that mediate reovirus-specific cytotoxicity are Thy-1+, Lyt-2+, and major histocompatibility complex (MHC)-restricted in their recognition of reovirus antigens, and can therefore be classified as CTLs. Frequency analysis of precursor CTLs occurring in Peyer's patches (PP) and peripheral lymph nodes (PLN) 6 d and 6 mo after intraduodenal stimulation have demonstrated that a persistent gradient of precursors is established, with higher frequencies present in PP. The generation of a CTL response in PP may be important in preferentially repopulating mucosal tissues with effector CTLs that could result in the local containment of infections in the gut. We also found that reovirus 1/L generates a virus-specific B cell response that is dominated by IgA memory cells after intraduodenal immunization. We hypothesize that the efficacy of reovirus 1/L at stimulating T and B cells in the gut mucosa is related to its ability to selectively enter PP via microfold (M) cells after enteric application. In this study we have also demonstrated that PP cells, upon in vitro culture and unrelated to prior reovirus priming, can generate natural killer-like (NK) cytotoxic activity. This may be an in vitro correlate of the in vivo generation of effectors that may populate mucosal tissues (i.e., the intestinal epithelium) with NK-like effector cells.

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