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PubMed2004

Alternative splicing in the first alpha-helical region of the Rab-binding domain of Rim regulates Rab3A binding activity: is Rim a Rab3 effector protein during evolution?

Rim1 and Rim2 were originally described as specific Rab3A-effector proteins involved in the regulation of secretory vesicle exocytosis. The putative Rab3A-binding domain (RBD) of Rim consists of two alpha-helical regions (named RBD1 and RBD2) separated by two zinc finger motifs. Although alternative splicing in the RBD1 of Rim is known to produce long and short forms of RBD (named Rim1 and Rim1Delta56-105, and Rim2(+40A) and Rim2, respectively), with the long form of Rim1 and short form of Rim2 being dominant in mouse brain, the physiological significance of the alternative splicing in RBD1 has never been elucidated. In the present study I discovered that alternative splicing in Rim RBD1 alters Rab3A binding affinity to Rims, and found that insertion of 40 amino acids into the RBD1 of Rim2 (i.e. Rim2(+40A)) dramatically reduced its Rab3A binding activity (more than a 50-fold decrease in affinity). Similarly, Rim1Delta56-105 exhibited higher affinity binding to Rab3A than the long form of Rim1. Expression of the short forms of the Rim RBD in PC12 cells co-localized well with endogenous Rab3A, whereas expression of the long forms of the Rim RBD in PC12 cells resulted in cytoplasimc and nuclear localization. Moreover, I found that Caenorhabditis elegans Rim/UNC-10 (ce-Rim) and Drosophila Rim (dm-Rim) do not interact with ce-Rab3 and dm-Rab3, respectively, indicating that the Rab3-effector function of Rim has not been retained during evolution. Based on these findings, I propose that the Rab3A-effector function of Rim during secretory vesicle exocytosis is limited to the short form of the mammalian Rim RBD alone.

Alternative Splicing↗
PubMed1976

Complex nature of the production of 'effector' cells and their interaction with target cells in the M-antigen system of the mouse.

The capacity of lymphocytes from mouse strain CBA to generate 'effector' cells against the H-2-compatible, M-antigen-incompatible strain C3H and their interaction with such target cells were investigated. It was observed that CBA lymphocytes injected in, and 5 days later obtained from, the spleens of irradiated C3H X CBA hybrids ('educated cells') could strongly inhibit the growth of C3H X CBA bone marrow cells but were almost nonresponsive to C3H X C57BI bone marrow targets (H-2-incompatible). CBA lymphocytes educated in irradiated C3H X C57BI hosts displayed reactivity against C3H X C57BI and CBA X C57BL but not against C3H X CBA bone marrow target cells. Additional tests indicated that the M antigen determined by C3H is expressed to approximately the same extent on C3H X CBA and C3H X C75BL cells and that the M antigen on C3H does not cross-react immunologically with antigens on C57BL cells. Moreover, it was observed that CBA X C57BI lymphocytes were triggered to cell proliferation by C3H antigens but were unable or had a highly reduced capacity to develop 'effector' cells in response to this antigenic stimulus. These results indicate that generation of 'effector' cells and their interaction with target cells are very complex processes.

Animals↗
PubMed1983

Characterization of effector cells mediating IgG and IgM antibody-dependent cellular cytotoxicity.

Spleen effector cells for IgG- and IgM-induced antibody-dependent cellular cytotoxicity (ADCC) were characterized with respect to density and cell surface markers by using sheep erythrocytes (SRBC) coated with hybridoma-derived monoclonal anti-SRBC IgG or anti-SRBC IgM antibodies as targets. While basically the same effector cells are cytolytic for IgG and IgM antibody-coated SRBC, they differ with respect to their relative killing capacity for IgG- versus IgM-coated target cells. On the basis of physical and biochemical properties three populations with cytolytic capacity could be separated: (I) A light fraction of large cells had high cytolytic potential for both IgG- and IgM-coated SRBC. The cells were negative for the Fc receptor for IgG (Fc gamma-R-) and the C3-receptor (C3-R-), they carried the receptor for Helix pomatia A agglutinin (HP-A+), and reactivity was strongly reduced after treatment with anti-Thy-1 and complement (C). (II) High activity was also observed with a medium-dense fraction, preferably lysing IgG antibody-coated cells. The cells were Fc gamma-R+, partly C3-R+, mostly HP-A-, and only a minor portion of the cells were Thy-1+. (III) A dense fraction, displaying on a per cell basis low cytolytic potential, was more active in IgM than IgG ADCC. The cells were Fc gamma-R+, HP-A+ and Thy-1+. All three effector cell populations were non-adherent, non-phagocytic, and surface immunoglobulin-negative (s-Ig-).

Animals↗
PubMed1983

Simultaneous determination of the concentration and lytic activity of effector cells that mediate natural and antibody-dependent cytotoxicity.

Cellular cytotoxicity reactions can be studied in a manner analogous to that used to measure enzyme activity. This approach yields two parameters: Vmax, the maximal rate of target cell lysis that can be achieved by the lymphocyte preparation tested, and KMapp, the apparent Michaelis constant. By analogy to many enzyme-catalysed reactions, KMapp values for cytotoxicity reactions have generally been interpreted in terms of dissociation constants for the interaction of receptor sites on effector cells with antigens on the target cells. In this paper we demonstrate that experimentally determined KMapp values for natural or antibody-dependent cytotoxicity reactions are approximately equal to the concentration of NK or K effector cells in the lymphocyte preparation tested. This result makes possible the simultaneous determination of both effector cell frequency and lytic activity in a given lymphocyte preparation.

Adult↗
PubMed1984

A quantitative assay detecting small numbers of effector helper T cells, regardless of clonal specificity.

We have developed a new assay for quantitative detection of all helper T cells that can induce normal B lymphocytes to proliferation and Ig secretion. To establish the optimal assay conditions, we have used cloned T helper cells of defined specificities that had previously been shown to activate normal B lymphocytes expressing the specific antigen(s) on direct cellular interactions. As shown in this paper, 'irrelevant' B lymphocytes--that is, those that do not express either antigen or restriction elements recognized by the effector helper T cells--can also be induced in the presence of appropriate concentrations of pokeweed mitogen which are not mitogenic for the 'target' B lymphocytes. 'Nonspecific' plaque-forming cell responses are of the same magnitude as those provided to specifically triggered targets and equal or better than those induced by lipopolysaccharide. The assay is highly sensitive and enables 'semi-quantitative' detection of less than 20-30 effector T cells per culture. Since effector helper T cells can be detected regardless of the clonal specificity, the assay appears useful for quantitative studies of various populations of T helper cells displaying mixed specificities and for the classification of cells with unknown functions.

Animals↗
PubMed2006

CD62L is required for the priming of encephalitogenic T cells but does not play a major role in the effector phase of experimental autoimmune encephalomyelitis.

CD62L (l-selectin, mel 14) regulates naïve T cell homing into lymph nodes and the migration of leucocytes to sites of inflammation. The requirement of CD62L in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, has been demonstrated previously. However, it remains controversial as to whether CD62L is required for the induction or the effector phase of EAE. It is also unclear whether other non-T effector cells need CD62L to enter the central nervous system (CNS) parenchyma and exert their damaging effects on myelin. We report that mice with a targeted mutation of CD62L are resistant to Myelin oligodendrocyte glycoprotein peptide-induced EAE. CD62L-deficient mice had no peptide-specific T cell responses in the draining lymph nodes and had lower levels of peptide-specific T cell responses in spleens at a later time point. Adoptive transfer studies showed that CD62L-deficient mice were fully susceptible to adoptive transfer EAE induced by either wildtype or CD62L-deficient T cells. Moreover, CD62L-deficient, F4/80(+) macrophages can be efficiently recruited into the CNS parenchyma. These data suggest that CD62L is required for the induction of encephalitogenic T cells during EAE development, but is not required by T and non-T effector cells to attack the CNS parenchyma.

Adoptive Transfer↗
PubMed2004

Activation of a COI1-dependent pathway in Arabidopsis by Pseudomonas syringae type III effectors and coronatine.

Gram-negative bacteria use a variety of virulence factors including phytotoxins, exopolysaccharides, effectors secreted by the type III secretion system, and cell-wall-degrading enzymes to promote parasitism in plants. However, little is known about how these virulence factors alter plant cellular responses to promote disease. In this study, we show that virulent Pseudomonas syringae strains activate the transcription of an Arabidopsis ethylene response factor (ERF) gene, RAP2.6, in a coronatine insensitive 1 (COI1)-dependent manner. A highly sensitive RAP2.6 promoter-firefly luciferase (RAP2.6-LUC) reporter line was developed to monitor activities of various bacterial virulence genes. Analyses of P. syringae pv. tomato DC3000 mutants indicated that both type III secretion system and the phytotoxin coronatine are required for RAP2.6 induction. We show that at least five individual type III effectors, avirulence B (AvrB), AvrRpt2, AvrPphB, HopPtoK, and AvrPphEPto, contributed to RAP2.6 induction. Gene-for-gene recognition was not involved in RAP2.6 induction because plants lacking RPM1 and RPS2 responded normally to AvrB and AvrRpt2 in RAP2.6 expression. Interestingly, the role of coronatine in RAP2.6 induction can be partially substituted by the addition of avrB in DC3000, suggesting that AvrB may mimic coronatine. These results suggest that P. syringae type III effectors and coronatine act by augmenting a COI1-dependent pathway to promote parasitism.

Amino Acids↗
PubMed2005

Pseudomonas syringae pv. tomato type III effectors AvrPto and AvrPtoB promote ethylene-dependent cell death in tomato.

The type III secretion system (TTSS) of Pseudomonas syringae pv. tomato (Pst) injects into the plant cell effector proteins that play an essential role in the formation of bacterial speck disease. To investigate the molecular roles of TTSS effectors in disease formation, we used a cDNA microarray to analyze the expression of approximately 8600 random tomato genes in response to wild-type Pst strain DC3000 and a mutant lacking a functional TTSS. Many of the differentially expressed genes identified encode proteins associated with hormone response or hormone biosynthesis pathways. Using isogenic mutant strains of DC3000, we monitored host transcriptional changes in response to the TTSS effector proteins AvrPto and AvrPtoB, both of which are important virulence factors on susceptible tomato lines. We found that AvrPto and AvrPtoB induce a set of host genes involved in ethylene biosynthesis and signaling, and in particular they regulate the expression of two genes, LeACO1 and LeACO2, encoding the ethylene-forming enzyme ACC oxidase. Analysis of transgenic tomato lines with diminished ACC oxidase activity revealed that ethylene production by the host is required for the full virulence activity of both AvrPto and AvrPtoB. AvrPto and AvrPtoB therefore appear to promote enhanced disease in tomato leaves, in part, by upregulating genes involved in ethylene production.

Bacterial Proteins↗
PubMed2005

Basal resistance against bacteria in Nicotiana benthamiana leaves is accompanied by reduced vascular staining and suppressed by multiple Pseudomonas syringae type III secretion system effector proteins.

Basal resistance in plants is induced by flagellin and several other common bacterial molecules and is implicated in the immunity of plants to most bacteria and other microbes. However, basal resistance can be suppressed by effector proteins that are injected by the type III secretion system (TTSS) of pathogens such as Pseudomonas syringae. This study demonstrates that basal resistance in the leaves of Nicotiana benthamiana is accompanied by reduced vascular flow into minor veins. Reduced vascular flow was assayed by feeding leaves, via freshly excised petioles, with 1% (weight in volume, w/v) neutral red (NR) and then observing differential staining of minor veins or altered levels of extractable dye in excised leaf samples. The reduced vascular staining was localized to tissues expressing basal resistance and was observable when resistance was induced by either the non-pathogen Pseudomonas fluorescens, a TTSS-deficient mutant of P. syringae pv. tabaci, or flg22 (a flagellin-derived peptide elicitor of basal resistance). Nicotiana benthamiana leaf areas expressing basal resistance no longer elicited the hypersensitive response when challenge inoculated with P. syringae pv. tomato DC3000. The reduced vascular staining effect was suppressed by wild-type P. syringae pv. tabaci and P. fluorescens heterologously expressing a P. syringae TTSS and AvrPto1(PtoJL1065). TTSS-proficient P. fluorescens was used to test the ability of several P. syringae pv. tomato DC3000 effectors for their ability to suppress the basal resistance-associated reduced vascular staining effect. AvrE(PtoDC3000), HopM1(PtoDC3000) (formerly known as HopPtoM), HopF2(PtoDC3000) (HopPtoF) and HopG1(PtoDC3000) (HopPtoG) suppressed basal resistance by this test, whereas HopC1(PtoDC3000) (HopPtoC) did not. In summary, basal resistance locally alters vascular function and the vascular dye uptake assay should be a useful tool for characterizing effectors that suppress basal resistance.

Bacterial Proteins↗
PubMed2004

Effector proteins encoded by Salmonella pathogenicity island 2 interfere with the microtubule cytoskeleton after translocation into host cells.

The facultative intracellular pathogen Salmonella enterica has evolved strategies to modify its fate inside host cells. One key virulence factor for the intracellular pathogenesis is the type III secretion system encoded by Salmonella Pathogenicity Island 2 (SPI2). We have previously described SPI2-encoded SseF and SseG as effector proteins that are translocated by intracellular Salmonella. Detailed analysis of the subcellular localization of SseF and SseG within the host cell indicated that these effector proteins are associated with endosomal membranes as well as with microtubules. Specific association with microtubules was observed after translocation by intracellular Salmonella as well as after expression by transfection vectors. In epithelial cells infected with Salmonella, both SseF and SseG are required for the aggregation of endosomal compartments along microtubules and to induce the formation of massive bundles of microtubules. These observations demonstrate that SPI2 effectors interfere with the microtubule cytoskeleton and suggest that microtubule-dependent host cell functions such as vesicle transport or organelle positioning are altered by intracellular Salmonella.

Bacterial Proteins↗
PubMed1982

The reactions between active and inactive forms of wheat ribulosebisphosphate carboxylase and effectors.

The processes of activation and deactivation of ribulose-1,5-bisphosphate carboxylase purified from wheat have been investigated. Two forms of the enzyme are indistinguishable in terms of ribulose-1,5-bisphosphate carboxylation and oxidation but exhibit different rates of activation. One form is slowly activated in saturating CO2 and Mg2+ at moderate temperatures (t0.5 approximately 120 min at 25 degrees C), the other form rapidly activated (t0.5 approximately 8 s). In the presence of the effectors 6-phosphogluconate or NADPH, significantly lower concentrations of the activating co-factors can achieve full activation of both enzyme species. However, with another effector, fructose 1,6-bisphosphate, for the slowly activating species the mode of action is the same as with 6-phosphogluconate or NADPH, whereas the activation of the rapidly activating species is significantly inhibited. The substrate, ribulose 1,5-bisphosphate, also inhibits this rapid activation process. A mechanism is proposed for the reactions involving activation that accounts for the differential rates of activation and the response to effectors.

Carboxy-Lyases↗
PubMed1984

Interaction of calmodulin with muscle phosphofructokinase. Interplay with metabolic effectors of the enzyme under physiological conditions.

The hysteretic calmodulin-induced inactivation of muscle phosphofructokinase and the calmodulin-mediated reactivation are essentially dependent on environmental conditions. The interplay of calmodulin during these reactions and at allosteric conditions with Mg . ATP, fructose 6-phosphate, adenosine 5'-[beta, gamma-imido]triphosphate and with the allosteric effectors AMP, ADP, fructose 1,6-bisphosphate, fructose 2,6-bisphosphate and glucose 1,6-bisphosphate was studied by two techniques. (a) A two-step technique with a preincubation of enzyme, calmodulin and effectors in close to physiological concentrations before dilution into an optimal activity assay. It reveals aggregation and slowly reversible conformation changes. (b) A direct assay of dilute enzyme at allosteric conditions. Dominating in the interplay of calmodulin with metabolic effectors is the competitive-like action of calmodulin on Mg . ATP binding to the regulatory sites of the enzyme. At high enzyme concentrations in the absence of hexose phosphates, i.e. at noncatalytic conditions calmodulin counteracts the stabilization of the highly active tetrameric form caused by Mg . ATP. In the allosteric assay it counteracts the ATP-induced allosteric inhibition. In both cases calmodulin acts synergistic with AMP and ADP. To a minor degree calmodulin also counteracts the stabilization of the tetrameric form caused by fructose 6-phosphate and hexose bisphosphate, now however antagonistically to AMP and ADP. By the demonstrated interactions the enzyme can be slowly and hysteretically shifted between an active tetrameric and an inactive dimeric state under control metabolic conditions and of Ca2+ and calmodulin. Resting conditions will inactivate and high contractile activity reactivate available enzyme.

Adenosine Triphosphate↗
PubMed1996

Role of the insulin receptor C-terminal acidic domain in the modulation of the receptor kinase by polybasic effectors.

Basic polymers such as polylysine have been found to activate insulin receptor autophosphorylation and kinase activity toward substrates. It was suggested that acidic receptor domains may be involved in the interaction of the receptor with these basic effectors. In a previous study, we have shown that the receptor acid-rich C-terminal sequence, including residues 1270-1280, is involved in the regulation of the receptor kinase activity. Moreover, this domain may be the site of interaction with histone, which is a modulator of the receptor kinase. In this study, we investigated whether the insulin receptor domain comprising amino acids 1270-1280 is involved in the interaction with polybasic effectors. We used anti-peptide serum directed to this sequence, and basic activators such as polylysine, polyarginine and protamine sulfate. Our antibodies inhibit polylysine-induced receptor autophosphorylation, whereas they have no effect on receptor phosphorylation stimulated by concanavalin A which is a non-basic activator of the insulin receptor. Polylysine-induced receptor aggregation was blocked by the antibodies (Fab fragments or whole Ig), indicating that competition occurs between the antibody and polylysine at the level of their binding site to the receptor. Finally, we observed a direct interaction of the 125I-peptide corresponding to receptor sequence 1270-1280 with the basic polymers in dot-blot experiments. Interestingly, the peptide did not bind spermine, a basic molecule which is not an activator of the insulin receptor kinase. Our data indicate that the insulin receptor C-terminal acidic domain including residues 1270-1280 is involved in the interaction of polylysine and other polybasic molecules with the receptor. Since this receptor region has been implicated in the regulation of the receptor kinase activity, we propose that interaction of basic effectors with this domain may be responsible for their activating properties.

Antibodies↗
PubMed1996

Flavin motion in p-hydroxybenzoate hydroxylase. Substrate and effector specificity of the Tyr22-->Ala mutant.

The side chain of Tyr222 in p-hydroxybenzoate hydroxylase interacts with the carboxy moiety of the substrate. Studies on the Tyr222-->Phe mutant, [F222]p-hydroxybenzoate hydroxylase, have shown that disruption of this interaction hampers the hydroxylation of 4-hydroxybenzoate. Tyr222 is possibly involved in flavin motion, which may facilitate the exchange of substrate and product during catalysis. To elucidate the function of Tyr222 in more detail, in the present study the substrate and effector specificity of the Tyr222-->Ala mutant, [A222]p-hydroxybenzoate hydroxylase, was investigated. Replacement of Tyr222 by Ala impairs the binding of the physiological substrate 4-hydroxybenzoate and the substrate analog 4-aminobenzoate. With these compounds, [A222]p-hydroxybenzoate hydroxylase mainly acts as a NADPH oxidase. [A222]p-hydroxybenzoate hydroxylase tightly interacts with 2,4-dihydroxybenzoate and 2-hydroxy-4-aminobenzoate. Crystallographic data [Schreuder, H.A., Mattevi, A., Oblomova, G., Kalk, K.H., Hol, W.G.J., van der Bolt, F.J.T. & van Berkel, W.J.H. (1994) Biochemistry 33, 10161-10170] suggest that this is due to motion of the flavin ring out of the active site, allowing hydrogen-bond interaction between the 2-hydroxy group of the substrate analogs and N3 of the flavin. [A222]p-Hydroxybenzoate hydroxylase produces about 0.6 mol 2,3,4-trihydroxybenzoate from 2,4-dihydroxybenzoate/mol NADPH oxidized. This indicates that reduction of the Tyr222-->Ala mutant shifts the equilibrium of flavin conformers towards the productive "in' position. [A222]p-Hydroxybenzoate hydroxylase converts 2-fluoro-4-hydroxybenzoate to 2-fluoro-3,4-dihydroxybenzoate. The regioselectivity of hydroxylation suggests that [A222]p-hydroxybenzoate hydroxylase binds the fluorinated substrate in the same orientation as wild-type. Spectral studies suggest that wild-type and [A222]p-hydroxybenzoate hydroxylase bind 2-fluoro-4-hydroxybenzoate in the phenolate form with the flavin ring preferring the "out' conformation. Despite activation of the fluorinated substrate and in contrast to the wild-type enzyme, [A222]p-hydroxybenzoate hydroxylase largely produces hydrogen peroxide. The effector specificity of p-hydroxybenzoate hydroxylase is not changed by the Tyr222-->Ala replacement. This supports the idea that the effector specificity is mainly dictated by the protein-substrate interactions at the re-side of the flavin ring.

4-Hydroxybenzoate-3-Monooxygenase↗
PubMed2006

A Salmonella type III secretion effector interacts with the mammalian serine/threonine protein kinase PKN1.

Essential to salmonellae pathogenesis is an export device called the type III secretion system (TTSS), which mediates the transfer of bacterial effector proteins from the bacterial cell into the host cell cytoplasm. Once inside the host cell, these effectors are then capable of altering a variety of host cellular functions in order to promote bacterial survival and colonization. SspH1 is a Salmonella enterica serovar Typhimurium TTSS effector that localizes to the mammalian nucleus and down-modulates production of proinflammatory cytokines by inhibiting nuclear factor (NF)-kappaB-dependent gene expression. To identify mammalian binding partners of SspH1 a yeast two-hybrid screen against a human spleen cDNA library was performed. It yielded a serine/threonine protein kinase called protein kinase N 1 (PKN1). The leucine-rich repeat domain of SspH1 was demonstrated to mediate this interaction and also inhibition of NF-kappaB-dependent gene expression. This suggested that PKN1 may play a role in modulation of the NF-kappaB signalling pathway. Indeed, we found that expression of constitutively active PKN1 in mammalian cells results in a decrease, while depletion of PKN1 by RNA interference causes an increase in NF-kappaB-dependent reporter gene expression. These data indicate that SspH1 may inhibit the host's inflammatory response by interacting with PKN1.

Animals↗
PubMed2006

Salmonella enterica serovar Typhimurium effectors SopB, SopE, SopE2 and SipA disrupt tight junction structure and function.

Salmonella enterica serovar Typhimurium is a major cause of human gastroenteritis. Infection of epithelial monolayers by S. Typhimurium disrupts tight junctions that normally maintain the intestinal barrier and regulate cell polarity. Tight junction disruption is dependent upon the Salmonella pathogenicity island-1 (SPI-1) type 3 secretion system but the specific effectors involved have not been identified. In this study we demonstrate that SopB, SopE, SopE2 and SipA are the SPI-1-secreted effectors responsible for disruption of tight junction structure and function. Tight junction disruption by S. Typhimurium was prevented by inhibiting host protein geranylgeranylation but was not dependent on host protein synthesis or secretion of host-derived products. Unlike wild-type S. Typhimurium, DeltasopB, DeltasopE/E2, DeltasipA, or DeltasipA/sopB mutants, DeltasopB/E/E2 and DeltasipA/sopE/E2 mutants were unable to increase the permeability of polarized epithelial monolayers, did not disrupt the distribution or levels of ZO-1 and occludin, and did not alter cell polarity. These data suggest that SPI-1-secreted effectors utilize their ability to stimulate Rho family GTPases to disrupt tight junction structure and function.

Animals↗
PubMed1986

Immunoactive products of placenta. V: Soluble factors from murine placenta can block effector stages of maternal antipaternal cell-mediated immunity.

Supernatants from short-term cultures of placental or trophoblast-enriched cell suspensions derived from 14-17-day isopregnant mice display suppressive activity on NK lysis in vitro. The soluble factor is produced by trypsin-sensitive cells and requires protein synthesis. Its activity is destroyed by treatment with insoluble trypsin. The suppression is not strain restricted, but appears species-restricted. The factor acts at the level of the NK effectors themselves. Furthermore, such supernatants also are able to inhibit CTL-mediated lysis at the effector stage, in an MHC nonrestricted, nonspecific fashion. The effect is not seen with supernatants from control fetal tissues. At least two mechanisms could be involved: inhibition of homing toward allogeneic targets, and a direct effect on effector cell lytic action. These factors could play an important role in protecting the placenta from the deleterious effects of maternal antipaternal immunity and could explain the survival of the fetus in a presensitized maternal host.

Animals↗
PubMed2001

Priming of memory but not effector CD8 T cells by a killed bacterial vaccine.

Killed or inactivated vaccines targeting intracellular bacterial and protozoal pathogens are notoriously ineffective at generating protective immunity. For example, vaccination with heat-killed Listeria monocytogenes (HKLM) is not protective, although infection with live L. monocytogenes induces long-lived, CD8 T cell-mediated immunity. We demonstrate that HKLM immunization primes memory CD8 T lymphocyte populations that, although substantial in size, are ineffective at providing protection from subsequent L. monocytogenes infection. In contrast to live infection, which elicits large numbers of effector CD8 T cells, HKLM immunization primes T lymphocytes that do not acquire effector functions. Our studies show that it is possible to dissociate T cell-dependent protective immunity from memory T cell expansion, and that generation of effector T cells may be necessary for long-term protective immunity.

Animals↗