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At least 127 records · Page 7Linked to original sources
PubMed2001

Production of interferon-gamma by influenza hemagglutinin-specific CD8 effector T cells influences the development of pulmonary immunopathology.

This study examined the inflammation, lung function impairment, and immune protection associated with either wild-type or interferon (IFN)-gamma-deficient Tc1- or Tc2-CD8 effector cells responding to influenza pneumonia. The adoptive transfer of influenza hemagglutinin-specific Tc1 effectors afforded protection and elicited only minimal impairment of lung function. IFN-gamma-deficient Tc1 effector cells were equally protective, but were associated with an eosinophil influx and slightly more lung function impairment early in the response. Relative to Tc1, Tc2 effector cells were less protective, elicited an eosinophil influx and a greater impairment of lung functions. IFN-gamma-deficient Tc2 effector cells were not protective and were associated with the severest impairment of lung function throughout the response, an accumulation of neutrophils, and extensive pulmonary vasculitis and alveolar hemorrhaging. Deletion of IFN-gamma was associated with a delay in effector cell recruitment and the elicitation of a more intense inflammatory response that resulted in more severe lung function impairment in the recipients of either Tc1 or Tc2 IFN-gamma-deficient effector cells. Thus, during influenza infections, IFN-gamma production by the responding CD8 T cells is associated with effector cell recruitment and mitigation of the associated inflammation and of the resulting impairment in lung functions but is not necessary for optimal protection.

Animals↗
PubMed2002

Study of the physical meaning of the binding parameters involved in effector-target conjugation using monoclonal antibodies against adhesion molecules and cholera toxin.

In earlier work, we established a mathematical model to characterize the binding properties of cytotoxic cells to target cells. These properties can be described by the values of the maximum effector and target conjugate frequencies, alpha(max) and beta(max), respectively, and the dissociation constant of the conjugates formed, K(D) (Garcia-Peñarrubia, P., Cabrera, L., Alvarez, R., and Galvez, J., J. Immunol. Methods 155 (1992) 133). Here, we address the problem of exploring the physical meaning of these parameters and their relationships with cytotoxicity. With this purpose, conjugation between a human leukemic NK cell line (NKL) and K562 tumor cells has been studied from binding isotherms obtained from data of effector (alpha) and target (beta) conjugate frequencies measured by flow cytometry analysis at different effector-to-target ratios (R). The results have been compared to those obtained after target cells treatment with monoclonal antibodies recognizing adhesion molecules ICAM-1 (CD54) and LFA-3 (CD58) (which are able to block some of the receptors implicated in conjugation), as well as with cholera toxin (CTX) that can modify the state of affinity of some adhesion molecules such as LFA-1 (CD11a/CD18). The results show that: (1) blocking adhesion receptors CD54 and CD58 on the surface of target cells leads to a significant decrease of alpha(max) and beta(max), indicating that these parameters are related to the density of expression of receptors implicated in effector-target adhesion; (2) treatment of effector cells with CTX induced an increase of K(D), demonstrating that this parameter is associated with the effector-target affinity of the system; and (3) parallel experiments of conjugation and cytotoxicity showed that effector-target affinity and saturability influence the cytotoxic activity of the effector population.

Adult↗
PubMed2006

Characterization of interactions between ras family GTPases and their effectors.

Ras family GTPases (RFGs), when in their active GTP-bound state, interact with a wide array of downstream effectors to regulate many biological functions in different cell types. How signal specificity among the closely related family members is achieved is still poorly understood. There is both promiscuity and specificity in the ability of RFGs to interact with and regulate the various effector families, as well as isoforms within those families. RFGs seem to have individual blueprints of effector interactions, and specificity should be considered in the context of the full spectrum of effectors they regulate. The sequencing of the genome has identified a remarkably diverse number of proteins with domains homologous to the Ras-binding domain (RBD) of known Ras effectors and, thus, with the potential to interact with Ras and/or other RFGs. In addition, other proteins without known RBD types are known to behave as RFG effectors, suggesting even more complexity in the number of effector interactions. Determining which of these many candidates are "true" effectors and characterizing their specificity is a critical step to understanding the specific signaling properties and biological functions of the various RFGs.

Animals↗
PubMed2005

A high-throughput, near-saturating screen for type III effector genes from Pseudomonas syringae.

Pseudomonas syringae strains deliver variable numbers of type III effector proteins into plant cells during infection. These proteins are required for virulence, because strains incapable of delivering them are nonpathogenic. We implemented a whole-genome, high-throughput screen for identifying P. syringae type III effector genes. The screen relied on FACS and an arabinose-inducible hrpL sigma factor to automate the identification and cloning of HrpL-regulated genes. We determined whether candidate genes encode type III effector proteins by creating and testing full-length protein fusions to a reporter called Delta79AvrRpt2 that, when fused to known type III effector proteins, is translocated and elicits a hypersensitive response in leaves of Arabidopsis thaliana expressing the RPS2 plant disease resistance protein. Delta79AvrRpt2 is thus a marker for type III secretion system-dependent translocation, the most critical criterion for defining type III effector proteins. We describe our screen and the collection of type III effector proteins from two pathovars of P. syringae. This stringent functional criteria defined 29 type III proteins from P. syringae pv. tomato, and 19 from P. syringae pv. phaseolicola race 6. Our data provide full functional annotation of the hrpL-dependent type III effector suites from two sequenced P. syringae pathovars and show that type III effector protein suites are highly variable in this pathogen, presumably reflecting the evolutionary selection imposed by the various host plants.

Arabidopsis↗
PubMed1999

Novel effector control through modulation of a preexisting binding site of the aromatic-responsive sigma(54)-dependent regulator DmpR.

The Pseudomonas derived sigma(54)-dependent DmpR activator regulates transcription of the (methyl)phenol catabolic dmp-operon. DmpR is constitutively expressed, but its transcriptional promoting activity is positively controlled in direct response to the presence of multiple aromatic effectors. Previous work has led to a model in which effector binding by the amino-terminal region of the protein relieves repression of an intrinsic ATPase activity essential for its transcriptional promoting property. Here, we address whether the observed differences in the potencies of the multiple effectors (i) reside at the level of different aromatic binding sites, or (ii) are mediated through differential binding affinities; furthermore, we address whether binding of distinct aromatic effectors has different functional consequences for DmpR activity. These questions were addressed by comparing wild type and an effector specificity mutant of DmpR with respect to effector binding characteristics and the ability of aromatics to elicit ATPase activity and transcription. The results demonstrate that six test aromatics all share a common binding site on DmpR and that binding affinities determine the concentration at which DmpR responds to the presence of the effector, but not the magnitude of the responses. Interestingly, this analysis reveals that the novel abilities of the effector specificity mutant are not primarily due to acquisition of new binding abilities, but rather, they reside in being able to productively couple ATPase activity to transcriptional activation. The mechanistic implications of these findings in terms of aromatic control of DmpR activity are discussed.

Adenosine Triphosphatases↗
PubMed2004

Semihemoglobins, high oxygen affinity dimeric forms of human hemoglobin respond efficiently to allosteric effectors without forming tetramers.

Significant reduction in oxygen affinity resulting from interactions between heterotropic allosteric effectors and hemoglobin in not only the unligated derivative but also the fully ligated form has been reported (Tsuneshige, A., Park, S. I., and Yonetani, T. (2002) Biophys. Chem. 98, 49-63; Yonetani, T., Park, S. I., Tsuneshige, A., Imai, K., and Kanaori, K. (2002) J. Biol. Chem. 277, 34508-34520). To further investigate this effect in more detail, alpha- and beta-semihemoglobins, namely, alpha(heme)beta(apo) and alpha(apo)beta(heme), respectively, were prepared and characterized with respect to the impact of allosteric effectors on both conformation and ligand binding properties. Semihemoglobins are dimers characterized by a high affinity for oxygen and lack of cooperativity. We found that, compared with stripped conditions, semihemoglobins responded to effectors (inositol hexaphosphate and L35) by decreasing the affinity for oxygen by 60- and 130-fold for alpha- and beta-semihemoglobins, respectively. 1H NMR and sedimentation velocity experiments carried out with their ligated and unligated forms in the absence and presence of effectors revealed that semihemoglobins always remain as single-heme-carrying dimers. Recombination kinetics of their photolyzed CO derivatives showed that effectors did indeed interact with their ligated forms. Measurements of the Fe-His stretching mode show that the semihemoglobins undergo a large ligand binding-induced conformational shift and that both ligand-free and ligand derivatives respond to the presence of effectors. Contradictions to the Monod-Wyman-Changeaux/Perutz allosteric model arise since 1) the modulation of ligand affinity is not achieved in semihemoglobins by the formation of a low affinity T conformation (quaternary effect) but by direct interaction with effectors, 2) effectors do interact significantly with ligated forms of high affinity semihemoglobins, and 3) modulation of the ligand affinity and the cooperativity are not necessarily linked but instead can be separated into two distinct phenomena that can be isolated.

Allosteric Site↗
PubMed2006

Allosteric effectors influence the tetramer stability of both R- and T-states of hemoglobin A.

The contribution of heterotropic effectors to hemoglobin allostery is still not completely understood. With the recently proposed global allostery model, this question acquires crucial significance, because it relates tertiary conformational changes to effector binding in both the R- and T-states. In this context, an important question is how far the induced conformational changes propagate from the binding site(s) of the allosteric effectors. We present a study in which we monitored the interdimeric interface when the effectors such as Cl-, 2,3-diphosphoglycerate, inositol hexaphosphate, and bezafibrate were bound. We studied oxy-Hb and a hybrid form (alphaFeO2)2-(betaZn)2 as the T-state analogue by monitoring heme absorption and Trp intrinsic fluorescence under hydrostatic pressure. We observed a pressure-dependent change in the intrinsic fluorescence, which we attribute to a pressure-induced tetramer to dimer transition with characteristic pressures in the 70-200-megapascal range. The transition is sensitive to the binding of allosteric effectors. We fitted the data with a simple model for the tetramer-dimer transition and determined the dissociation constants at atmospheric pressure. In the R-state, we observed a stabilizing effect by the allosteric effectors, although in the T-analogue a stronger destabilizing effect was seen. The order of efficiency was the same in both states, but with the opposite trend as inositol hexaphosphate > 2,3-diphosphoglycerate > Cl-. We detected intrinsic fluorescence from bound bezafibrate that introduced uncertainty in the comparison with other effectors. The results support the global allostery model by showing that conformational changes propagate from the effector binding site to the interdimeric interfaces in both quaternary states.

2,3-Diphosphoglycerate↗
PubMed2003

Novel exchangeable effector loci associated with the Pseudomonas syringae hrp pathogenicity island: evidence for integron-like assembly from transposed gene cassettes.

Pseudomonas syringae strains use a type III secretion system (TTSS) to translocate effector proteins that assist in the parasitism of host plant cells. Some genes for effector proteins are clustered in the exchangeable effector locus (EEL) associated with the hrp pathogenicity island. A polymerase chain reaction-based screen was developed to amplify the EEL from P. syringae strains. Of the 86 strains screened, the EEL was successfully amplified from 30 predominately North American P. syringae pv. syringae strains using hrpK and queA-derived primers and from an additional three strains using hrpL and queA-derived primers. Among the amplified EEL, ten distinct types of EEL were identified that could be classified into six families distinguishable by genetic composition, but other types of EEL may be present in strains isolated in other geographical regions. No linkage with the host range of the source strain was apparent. Gene cassettes carrying conserved flanking, coding, and intergenic sequences, present in different combinations, were identified in the characterized EEL. Six new alleles of known effectors were identified that differed from the homolog in sequence, size, or both of the gene. One of these apparently novel effector proteins, HopPsyB, retained a strongly conserved amino terminus similar to that of HopPsyA, but other regions of the two polypeptides were only weakly similar. hopPsyB was expressed from an apparent operon that included hrpK and a shcA homolog, shcB. Escherichia coli MC4100 expressing the hrp TTSS, ShcB, and HopPsyB elicited the hypersensitive response (HR) in tobacco, consistent with effector production. Indicative of translocation as an effector, P. syringae pv. tomato DC3000 expressing a HopPsyB':'AvrRpt2 fusion elicited the HR in RPS2+ Arabidopsis thaliana. P. syringae pv. tomato DC3000 carrying HopPsyB exhibited slightly enhanced virulence in several Brassica spp. These results are consistent with the hypotheses that the EEL is a source of disparate effectors functioning in pathogenicity of P. syringae strains and that it evolved independently of the hrp pathogenicity island central conserved region, most likely through integron-like assembly of transposed gene cassettes.

Amino Acid Sequence↗
PubMed1994

Lysis of porcine trophoblast cells by endometrial natural killer-like effector cells in vitro does not require interleukin-2.

Cells with cytotoxic activity against the cell line K562 and expressing perforin have been demonstrated in endometrial cells isolated from pigs early in pregnancy. This study was designed to determine whether porcine trophoblast cells were susceptible to these endometrial effector cells in vitro. Pregnant gilts (n = 8) were slaughtered between Days 17 and 20 of gestation. Immediately after slaughter, both the endometrial effector cells and trophoblast cells were isolated enzymatically from each animal. Enzymatically dispersed endometrial cells were further fractionated by size at unit gravity, whereas trophoblast cells were enriched by discontinuous density centrifugation on Percoll. Cytolytic activity was evaluated against Na2 51CrO4-labeled trophoblast and K562 cells. Comparison was made between freshly prepared and interleukin-2 (IL-2)-stimulated effector cells. The effect of prostaglandin E2 (PGE2) was tested by including it directly in the 51Cr-release assay. The results indicated that porcine trophoblast cells, like K562 cells, could be recognized and directly lysed by endometrial effector cells. Preculture of effector cells with IL-2 was not required for target lysis but enhanced their cytolytic activity against both trophoblast and K562 targets. In contrast, PGE2 exhibited highly suppressive effects on the cytotoxic activity of both freshly isolated and IL-2-stimulated endometrial effector cells. Conjugate assays demonstrated the binding of trophoblast and K562 targets by effector cells of similar morphology. Cold-target inhibition assays suggested that the effectors in porcine endometrial cell preparations that killed trophoblast and K562 cells were the same NK cell-like population.

Animals↗
PubMed2006

The type III effector repertoire of Pseudomonas syringae pv. syringae B728a and its role in survival and disease on host and non-host plants.

The bacterial plant pathogen Pseudomonas syringae injects a large repertoire of effector proteins into plant cells using a type III secretion apparatus. Effectors can trigger or suppress defences in a host-dependent fashion. Host defences are often accompanied by programmed cell death, while interference with defences is sometimes associated with cell death suppression. We previously predicted the effector repertoire of the sequenced bean pathogen P. syringae pv. syringae (Psy) B728a using bioinformatics. Here we show that PsyB728a is also pathogenic on the model plant species Nicotiana benthamiana (tobacco). We confirm our effector predictions and clone the nearly complete PsyB728a effector repertoire. We find effectors to have different cell death-modulating activities and distinct roles during the infection of the susceptible bean and tobacco hosts. Unexpectedly, we do not find a strict correlation between cell death-eliciting and defence-eliciting activity and between cell death-suppressing activity and defence-interfering activity. Furthermore, we find several effectors with quantitative avirulence activities on their susceptible hosts, but with growth-promoting effects on Arabidopsis thaliana, a species on which PsyB728a does not cause disease. We conclude that P. syringae strains may have evolved large effector repertoires to extend their host ranges or increase their survival on various unrelated plant species.

Bacterial Proteins↗
PubMed1978

Ultrastructure of effector--target cell interaction in secondary cell-mediated lympholysis.

The ultrastructure of the secondary cell-mediated lympholysis (CML) reaction and the effects on interacting lymphocytes of colchicine, cytochalasin B, and effector cell-specific antisera were examined using transmission and scanning electron microscopy. Surface labelling of cytotoxic secondary effector cells with cationized ferritin allowed them to be distinguished from unlabelled target lymphocytes. Effector--target interactions were characterized by intercellular junctions involving extensive areas of membrane apposition and interdigitation and extension of pseudopod-like processes by the effector cell. The abolition of such interactions when effector populations were pretreated with anti-Ly2 sera plus complement demonstrated target cell destruction in secondary CML to be dependent on the activity of restimulated cytotoxic T lymphocytes. Cytochalasin B and colchicine dramatically decreased the numbers of specific effector--target cell interactions observed. Although the data presented do not allow the possible activity of soluble lytic factors associated with the effector cell surface to be ruled out, they suggest that target cell lysis in the secondary CML system examined results from immune-specific binding of alloantigen-sensitized effectors to targets and osmotic effects which follow localized disruption of the target cell membrane.

Animals↗
PubMed2001

Lack of expansion of major histocompatibility complex class Ib-restricted effector cells following recovery from secondary infection with the intracellular pathogen Listeria monocytogenes.

Sublethal infection of BALB/c mice with the intracellular bacterial pathogen Listeria monocytogenes leads to the development of antilisterial immunity with concurrent stimulation of major histocompatibility complex (MHC) class Ia- and Ib-restricted CD8+ effector T cells. Secondary L. monocytogenes infection is followed by an accelerated increase in the number of Listeria-specific CD8+ cells and rapid clearance of the bacterium from the murine host. Recovery from secondary infection is associated with increased levels of effector cell function, as measured by gamma interferon secretion following coculture of immune cells with L. monocytogenes infected APCs in vitro, as well as antilisterial cytotoxicity, as measured by effector cell recognition of L. monocytogenes-infected target cells. We assessed the frequency of L. monocytogenes-specific MHC class I-restricted cells following secondary infection by ELISPOT assays utilizing coculture of immune cells with L. monocytogenes-infected antigen-presenting cells that express MHC class Ia and/or Ib molecules. We found that the antilisterial Qa-1b (MHC class Ib)-restricted effector subset is not detected as an expanded population following secondary infection compared to the frequency of this effector population as measured following recovery from primary infection. This is in contrast to the frequency of antilisterial H2-Kd (MHC class Ia)-restricted effector cells, which following recovery from secondary infection are detected as an expanded population, and appears to undergo a substantial expansion event 3 to 4 days post-secondary infection. These results are consistent with the conclusion that although Listeria-specific MHC class Ib-restricted effector cells are present following recovery from secondary infection, this subset does not appear to undergo the expansion phase that is detected for the MHC class Ia-restricted effector cell response.

Animals↗
PubMed2005

Pseudomonas syringae type III chaperones ShcO1, ShcS1, and ShcS2 facilitate translocation of their cognate effectors and can substitute for each other in the secretion of HopO1-1.

The Pseudomonas syringae type III secretion system (TTSS) translocates effector proteins into plant cells. Several P. syringae effectors require accessory proteins called type III chaperones (TTCs) to be secreted via the TTSS. We characterized the hopO1-1, hopS1, and hopS2 operons in P. syringae pv. tomato DC3000; these operons encode three homologous TTCs, ShcO1, ShcS1, and ShcS2. ShcO1, ShcS1, and ShcS2 facilitated the type III secretion and/or translocation of their cognate effectors HopO1-1, HopS1, and HopS2, respectively. ShcO1 and HopO1-1 interacted with each other in yeast two-hybrid and coimmunoprecipitation assays. Interestingly, ShcS1 and ShcS2 were capable of substituting for ShcO1 in facilitating HopO1-1 secretion and translocation and each TTC was able to bind the other's cognate effectors in yeast two-hybrid assays. Moreover, ShcO1, ShcS1, and ShcS2 all bound to the middle-third region of HopO1-1. The HopS2 effector possessed atypical P. syringae TTSS N-terminal characteristics and was translocated in low amounts. A site-directed HopS2 mutation that introduced a common N-terminal characteristic from other P. syringae type III secreted substrates increased HopS2 translocation, supporting the idea that this characteristic functions as a secretion signal. Additionally, hopO1-2 and hopT1-2 were shown to encode effectors secreted via the DC3000 TTSS. Finally, a DC3000 hopO1-1 operon deletion mutant produced disease symptoms similar to those seen with wild-type DC3000 but was reduced in its ability to multiply in Arabidopsis thaliana. The existence of TTCs that can bind to dissimilar effectors and that can substitute for each other in effector secretion provides insights into the nature of how TTCs function.

Amino Acid Sequence↗
PubMed2006

Subterfuge and manipulation: type III effector proteins of phytopathogenic bacteria.

Diverse gram-negative bacteria deliver effector proteins into the cells of their eukaryotic hosts using the type III secretion system. Collectively, these type III effector proteins function to optimize the host cell environment for bacterial growth. Type III effector proteins are essential for the virulence of Pseudomonas syringae, Xanthomonas spp., Ralstonia solanacearum and Erwinia species. Type III secretion systems are also found in nonpathogenic pseudomonads and in species of symbiotic nitrogen-fixing Rhizobium. We discuss the functions of type III effector proteins of plant-associated bacteria, with an emphasis on pathogens. Plant pathogens tend to carry diverse collections of type III effectors that likely share overlapping functions. Several effectors inhibit host defense responses. The eukaryotic host targets of only a few type III effector proteins are currently known. We also discuss possible mechanisms for diversification of the suite of type III effector proteins carried by a given bacterial strain.

Apoptosis↗
PubMed2006

A catalogue of the effector secretome of plant pathogenic oomycetes.

The oomycetes form a phylogenetically distinct group of eukaryotic microorganisms that includes some of the most notorious pathogens of plants. Oomycetes accomplish parasitic colonization of plants by modulating host cell defenses through an array of disease effector proteins. The biology of effectors is poorly understood but tremendous progress has been made in recent years. This review classifies and catalogues the effector secretome of oomycetes. Two classes of effectors target distinct sites in the host plant: Apoplastic effectors are secreted into the plant extracellular space, and cytoplasmic effectors are translocated inside the plant cell, where they target different subcellular compartments. Considering that five species are undergoing genome sequencing and annotation, we are rapidly moving toward genome-wide catalogues of oomycete effectors. Already, it is evident that the effector secretome of pathogenic oomycetes is more complex than expected, with perhaps several hundred proteins dedicated to manipulating host cell structure and function.

Fungal Proteins↗
PubMed2003

Ex vivo characterization of human CD8+ T subsets with distinct replicative history and partial effector functions.

After antigenic challenge, naive T lymphocytes enter a program of proliferation and differentiation during the course of which they acquire effector functions and may ultimately become memory cells. In humans, the pathways of effector and memory T-cell differentiation remain poorly defined. Here we describe the properties of 2 CD8+ T-lymphocyte subsets, RA+CCR7-27+28+ and RA+CCR7-27+28-, in human peripheral blood. These cells display phenotypic and functional features that are intermediate between naive and effector T cells. Like naive T lymphocytes, both subsets show relatively long telomeres. However, unlike the naive population, these T cells exhibit reduced levels of T-cell receptor excision circles (TRECs), indicating they have undergone additional rounds of in vivo cell division. Furthermore, we show that they also share effector-type properties. At equivalent in vivo replicative history, the 2 subsets express high levels of Fas/CD95 and CD11a, as well as increasing levels of effector mediators such as granzyme B, perforin, interferon gamma, and tumor necrosis factor alpha. Both display partial ex vivo cytolytic activity and can be found among cytomegalovirus-specific cytolytic T cells. Taken together, our data point to the presence of T cells with intermediate effector-like functions and suggest that these subsets consist of T lymphocytes that are evolving toward a more differentiated effector or effector-memory stage.

Adult↗
PubMed2002

The fate of effector T cells in vivo is determined during activation and differs for CD4+ and CD8+ cells.

Effector T cells generated in the mesenteric lymph nodes (mLN) are known to accumulate in mLN and the tissue drained by them after circulating in the blood. Their accumulation is due less to preferential entry into mLN but more to preferential proliferation within mLN. The factors regulating the proliferation of effector T cells in vivo are unclear, and it is unknown whether they are different for CD4(+) and CD8(+) effector T cells. Rat T cells from mLN or peripheral lymph nodes (pLN) were stimulated polyclonally via the TCR and CD28 and injected i.v. into congenic recipients. Using three-color flow cytometry and immunohistochemistry, they were identified in mLN, pLN, and blood over time, and proliferation was determined by measuring bromodeoxyuridine incorporation. Only effector mLN T cells showed a significantly increased proliferation rate after entry into mLN compared with that in pLN (2.4 +/- 1.8% vs 0.8 +/- 0.4%). Proliferation among the injected cells was higher when they had contact with dendritic cells within mLN (9.0 +/- 4.3%) than when they did not (4.1 +/- 2.1%). Furthermore, effector mLN T cells which were observed 56 days after injection maintained the capacity for preferential proliferation within mLN. Interestingly, CD4(+) effector mLN T cells proliferated at a higher rate (4.8 +/- 0.7%), remaining in mLN, whereas CD8(+) effector mLN T cells proliferated at a lower rate (3.3 +/- 1.0%) and were able to leave the mLN into the blood. Elucidating the factors regulating the proliferation of effector T cells in vivo will help to modify their distribution for therapeutic purposes.

Adoptive Transfer↗
PubMed2003

Homing to nonlymphoid tissues is not necessary for effector Th1 cell differentiation.

The differentiation of naive T cells into effector Th1 cells is a complex process that may proceed in two steps, commitment and development. Initial TCR engagement and IFN-gamma signaling instruct the T cells to commit to the Th1 lineage, while subsequent IL-12 and potentially TCR signaling induces final differentiation into irreversible, Th1 effector cells. In agreement with a multistep process of Th1 cell differentiation, effector Th1 cell generation requires repeated TCR and cytokine signaling, thus raising the possibility that commitment and differentiation processes may occur in two distinct anatomical sites, the lymphoid organ and the site of infection, respectively. We tested this possibility using a model of skin sensitization that permits a direct analysis of Ag-specific T cells both within lymphoid organs and at the site of sensitization. We show in this study that Ag presentation in the skin does not induce further differentiation of skin-infiltrating T cells that are highly divided and fully differentiated effector cells. Thus, effector Th1 cell differentiation is completed within lymphoid organs. In addition, we examined the heterogeneity of CD4 T cell responses in vivo through the analysis of the expression, by activated T cells, of different selectins, including P-selectin ligand and CD62L known to define separable effector populations. We delineated, in lymph nodes, at least five distinct subpopulations of activated CD4 T cells with different phenotypes and recirculation properties. Collectively, these results show that the lymphoid environment orchestrates T cell activation to generate a repertoire of effector T cells with a diversity of effector functions.

Animals↗