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Carboxyfluorescein diacetate succinimidyl ester and the virgin lymphocyte: a marriage made in heaven.
Carboxyfluorescein diacetate succinimidyl ester (CFSE) labelling of naïve lymphocyte populations provides unique insights into the immune response. The clonal nature of immune responses, necessitating clonal expansion to achieve a sufficiently large number of Ag-reactive effector cells, combined with the dependence of lymphocyte differentiation on cell division, underlie the usefulness of CFSE in understanding the factors that regulate responses both in vitro and in vivo. We have combined CFSE labelling with Ag receptor transgenic models, using seven channel flow cytometry to track the correlation between cell division and a number of other parameters, such as surface expression of activation markers, cytokine receptors and homing receptors, cytokine production, cytotoxic activity and indicators of apoptosis. Our data have allowed us to classify and understand immune responses in novel ways, suggesting many further avenues of enquiry and indicating previously unrecognized relationships between cell division and eventual cell fate.
Bacterial superantigens reactivate antigen-specific CD8+ memory T cells.
Superantigens stimulate naive CD4+ and CD8+ T cells in a TCR V beta-specific manner. However, it has been reported that memory T cells are unresponsive to superantigen stimulation. In this study, we show that staphylococcal enterotoxins (SE) can activate influenza virus-specific CD8+ memory cytotoxic T cells. In vivo SEB challenge of mice that had recovered from influenza virus infection (memory mice) resulted in the generation of vigorous influenza-specific cytotoxic T lymphocyte (CTL) activity and in vitro SEA or SEB stimulation of splenic T cells from memory mice, but not naive mice, also induced influenza-specific CTL. Analysis of the mechanism of activation suggested that although there may be a component of cytokine-mediated bystander activation, the CTL activity is largely generated in response to direct TCR engagement by superantigen. Moreover, influenza-specific CTL could be generated from purified CD8+ CD62L loCD44hi (memory phenotype) T cells cultured in the presence of T cell-depleted splenic antigen-presenting cells and SE. Purified CD8+ memory T cells also secreted lymphokines and synthesized DNA in response to superantigen. These results definitively demonstrate that CD8+ memory T cells respond to SE stimulation by proliferating and developing appropriate effector function. Furthermore, the data raise the possibility that otherwise inconsequential exposure to bacterial superantigens may perturb the CD8+ T cell memory pool.
Induction and recall of immune memory by mucosal immunization with a non-toxic recombinant enterotoxin-based chimeric protein.
Previous reports have suggested that peroral delivery of antigens chemically coupled to non-toxic recombinant enterotoxin B subunits, such as the cholera toxin B subunit (CTB), induces tolerance to the antigen that may be abrogated by the toxic enzyme activity of intact enterotoxins, such as cholera toxin (CT). The aim of this study was to examine the immunogenicity of a genetically coupled protein composed of the saliva-binding region (SBR) of the Streptococcus mutans surface antigen AgI/II and the non-toxic A2 and B subunits of CT (SBR-CTA2/B) compared with that of recombinant SBR admixed with CT (SBR + CT) and SBR chemically coupled to recombinant CTB (SBR-CTB) following peroral delivery by intragastric (i.g.) immunization. The results showed that i.g. immunization with SBR-CTA2/B, like SBR + CT, induced antigen-specific serum immunoglobulin G (IgG) and salivary IgA antibodies, and sensitized splenic T cells. Comparison studies with SBR-CTB produced serum IgG but not salivary IgA titres and failed to sensitize splenic cells. Immunization with SBR-CTA2/B via the intranasal route also primed for the recall of antigen-specific memory antibody responses 6 months later. These findings show that SBR-CTA2/B is an immunogenic, not tolerogenic, chimeric protein that can induce and recall antigen-specific memory responses upon mucosal immunization.
Functional phenotypes of T lymphocytes: adhesion, migration and memory--and suppression?
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Neonatal tolerance: towards an immunogenetic definition of self.
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Homing receptors and the control of lymphocyte migration.
The traffic of lymphocytes is controlled in part by the selective interaction of circulating lymphocytes with specialized high endothelial venule (HEV) cells at sites of lymphocyte exit from the blood. At least three independent receptor systems are responsible for controlling lymphocyte traffic to different lymphoid organs or to sites of inflammation: one mediates lymphocyte interaction with HEV in peripheral lymph nodes, another in mucosa-associated lymphoid tissues, and a third in inflamed synovium. The receptors mediating lymphocyte recognition of HEV in different organs appear to be structurally related yet antigenically and functionally distinct 90 kD glycoproteins. Receptors for lymph node HEV can function as mammalian lectins, and probably interact with specific carbohydrate ligands on high endothelial cells. Mouse and human homing receptors share both antigenic and structural features, indicating a high conservation of lymphocyte-endothelial recognition systems during evolution. They play an essential part in the immune process by controlling lymphocyte traffic during B- and T-cell differentiation, and by segregating effector cells derived from stimulation in different tissues, thus simultaneously increasing the efficiency of organ-specific immune responses and decreasing possibilities for autoimmune crossreactions. Homing receptors are also expressed by many mouse and human lymphoid neoplasms, and appear to play a role in lymphoma metastasis. Related if not identical receptors are expressed by other leukocyte types, including polymorphonuclear leukocytes, monocytes, and large granular lymphocytes (natural killer cells). Thus lymphocyte homing receptors are members of a family of glycoprotein receptors for endothelium that control the extravasation of lymphocytes as well as other leukocytes, and help regulate both non-specific and specific immune responses in vivo.
Antibodies to tooth allografts in H-2 matched mice.
Teeth were transplanted among mice which represented the best match possible between unrelated humans. Sera were examined for their ability to kill donor cells with the help of complement, to trigger complement-independent, cell-mediated cytolysis, and to agglutinate RBC. All responses were weak, but rejection correlated best with antibody-dependent cytolysis.
Analysis of human peripheral blood T lymphocytes proliferating in response to sensitizing antigens: effect of interleukin-2 (IL-2)-responsive bystander cells.
The contribution of interleukin-2 (IL-2)-responsive bystander cells to the proliferative responses of human peripheral blood T lymphocytes to antigens used for sensitization such as Purified Protein Derivative (PPD), Tetanus toxoid (T T) and Influenza virus was investigated. Marked proliferation of the unfractionated peripheral blood mononuclear cells (PBMC) was observed following stimulation with these antigens to which the individuals were known to have been sensitized previously. Depletion of large granular lymphocytes (LGL) from PBMC resulted in substantial reduction in the response of the lymphoid cells in proliferating to the antigens. Proliferation of the T4+T8- (helper)-enriched population, or T4+T8- subset depleted of any IL-2 receptor (IL-2R)-bearing lymphoid cells to these antigens was comparable to that of LGL-depleted PBMC cultures. Cell titration experiments of the blast cells generated from these cultures revealed that PBMC-derived population contained fewer antigen-reactive lymphocytes. These results, therefore, suggested that IL-2-responsive LGL through expansion affected the concentration of antigen-proliferating T cells in the antigen-stimulated PBMC cultures.
Selective delivery of augmented IL-2 receptor signals to responding CD8+ T cells increases the size of the acute antiviral response and of the resulting memory T cell pool.
CD8(+) T cells respond to IL-2 produced both endogenously and by CD4(+) Th during an antiviral response. However, IL-2R signals can potentially promote CD8(+) T cell death as well as proliferation, making it unclear whether IL-2R signals provide a predominantly positive or negative effect upon CD8(+) T cell responses to viral infection. To more precisely define the direct role of IL-2R signaling on CD8(+) T cells during the response to a virus, we examined the effect of delivering augmented IL-2R signals selectively to CD8(+) T cells responding to lymphocytic choriomeningitis virus infection. Although naive CD8(+) T cells are competent to produce IL-2, CD8(+) T cells lose this capacity upon differentiation into effector CD8(+) T cells. However, effector CD8(+) T cells do retain the capacity to produce GM-CSF upon Ag stimulation. Thus, to deliver enhanced autocrine IL-2R signals to CD8(+) T cells, we established a transgenic mouse strain expressing a chimeric GM-CSF/IL-2R (GMIL2R). As GM-CSF production is Ag dependent, the GMIL2R delivers an augmented IL-2R signal exclusively to CD8(+) T cells responding to Ag. Following lymphocytic choriomeningitis virus infection, GMIL2R transgenic mice exhibited an increase in both the peak CD8(+) T cell response achieved and the size of the resulting memory pool established. Upon secondary viral challenge, the GMIL2R also enhanced the proliferative response of memory CD8(+) T cells. Thus, our findings indicate that IL-2 delivery to responding CD8(+) T cells is a limiting factor in both the acute and memory antiviral responses.
IL-2 induces a competitive survival advantage in T lymphocytes.
The acquisition of long-term survival potential by activated T lymphocytes is essential to ensure the successful development of a memory population in the competitive environment of the lymphoid system. The factors that grant competitiveness for survival to primed T cells are poorly defined. We examined the role of IL-2 signals during priming of CD4(+) T cells in the induction of a long-lasting survival program. We show that Ag-induced cycling of CD4(+) IL-2(-/-) T cells is independent of IL-2 in vitro. However, IL-2(-/-) T cells failed to accumulate in large numbers and develop in effector cells when primed in the absence of IL-2. More importantly, Ag-activated IL-2(-/-) T cells were unable to survive for prolonged periods of time after adoptive transfer in unmanipulated, syngeneic mice. IL-2(-/-) T cells exposed to IL-2 signals during priming, however, acquired a robust and long-lasting survival advantage over cells that cycled in the absence of IL-2. Interestingly, this IL-2-induced survival program was required for long-term persistence of primed IL-2(-/-) T cells in an intact lymphoid compartment, but was unnecessary in a lymphopenic environment. Therefore, IL-2 enhances competitiveness for survival in CD4(+) T cells, thereby facilitating the development of a memory population.
The immune system in inflammatory bowel disease.
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Transplantation immunity in fishes: Agnatha, Chondrichthyes and Osteichthyes.
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[Pathogenesis of rheumatoid arthritis. Involvement of the humoral immune system--memory lymphocytes in synovial membranes].
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Memory T cells in transplantation: generation, function, and potential role in rejection.
The adaptive immune system is endowed with long-lived memory to recall previous antigen encounters and respond more effectively to them. Memory immune responses are mediated by antigen-specific memory T lymphocytes that exhibit enhanced function compared with naïve T cells that have never encountered antigen. While the generation of memory T cells specific for pathogens is beneficial in providing protective immunity, memory T cells specific for alloantigens can be deleterious to the recipient of a transplanted organ. In graft rejection, memory T cells mediate accelerated, "second-set" rejection and their presence has been associated with increased propensity for early rejection. Recent findings have demonstrated that alloreactive memory T cells can be generated via exposure to alloantigens, as well as stimuli that are cross-reactive with alloantigens, and are therefore likely present in "naïve" individuals. This review focuses on the characteristics of memory T cells which make them of special interest to the transplant community, including differential activation requirements, broad homing properties, and resistance to tolerance induction. The multiple ways in which memory T cells can contribute to early and late graft rejection are discussed, as well as potential targets for combating alloreactive memory to be considered in the future design of tolerance induction strategies.
Immune network at the edge of chaos.
Some time ago Jerne proposed a new theory to explain the basis of the immune system. He suggested the existence of a functional connected network, based on pattern recognition of the idiotypes carried by the lymphocytes, which is responsible for the self regulation of the immune system. Only 15-20% of the lymphocytes available in the immune repertoire will participate in this functional network, while the rest of the lymphocytes will be free to respond to any foreign antigen. Each individual immune repertoire will be different depending on the lymphocytes that participate in the connected network. Using a very simple cellular automata model of the immune repertoire dynamics we show that, although the usual regimes (stable and chaotic) attained by this automata, are not interesting from the biological point of view, the transition region, at the edge of chaos, is very appropriate to describe such dynamics. In this region we have obtained a functional connected network involving 10-20% of the lymphocytes available in the repertoire, as suggested by Jerne and others. The model also reproduces the immune system signature, the ensemble of different lymphocytes that each individual expresses in his immune repertoire, which varies from one individual to another. We show how the immune memory comes out as a consequence of the dynamics of the system. From our results we confirm and present evidence that the chaotic regime corresponds to a sort of non-healthy state, as has been suggested previously.
Mucosal memory B cells retain the ability to produce IgM antibodies 2 years after oral immunization.
In recent studies we have demonstrated that immunological B- and T-cell memory may be stimulated effectively by oral immunization, simply by admixing protein antigens with cholera toxin (CT) adjuvant. Here we extend information by employing a hapten-carrier system allowing us to separate B- and T-cell memory and to evaluate the requirement of memory T cells for effective reactivation of mucosal memory B cells. We found that 2 weeks following oral priming immunizations with dinitrophenyl-keyhole limpet haemocyanin (DNP-KLH) plus CT adjuvant, significant serum anti-DNP antibodies of IgG, IgA and IgM immunoglobulin classes were demonstrated. However, after 2 years only IgM anti-DNP antibodies could still be detected in serum. When memory lymphocytes were isolated from these mice, from both systemic and gut-associated lymphoid tissues, and challenged with antigen in vitro, vigorous IgM, but no IgG or IgA, anti-DNP production was observed. By contrast, when the DNP-KHL-primed memory mice were challenged in vivo by an oral booster immunization with DNP-KLH plus CT adjuvant, strong systemic IgG and local mucosal IgA anti-DNP responses were recorded, while IgM anti-DNP production was poor. Moreover, the mucosal memory B cells from DNP-KHL-immunized mice were more responsive in vivo to an oral booster immunization with the carrier-specific antigen, DNP-KLH, compared to that provided by an unrelated carrier, DNP-human serum albumin (HSA), which gave only poor mucosal and systemic anti-DNP B-cell responses. Taken together our data suggest that mucosal memory B cells are recirculating cells that have retained their ability to produce IgM antibodies and, therefore, have not undergone switch differentiation involving gene rearrangements with constant mu-chain deletions. Furthermore, mucosal B-cell memory and CD4+ T-cell memory are closely interconnected phenomena, requiring both components for effective expression and probably also for maintenance of immunological memory in the mucosal immune system.
CD8 and B cell memory: same strategy, same signals.
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