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At least 1,063 records · Page 59Linked to original sources
PubMed1986

Lymphokine-activated killer cells. Analysis of progenitors and effectors.

IL-2 has been examined for its ability to regulate lymphokine-activated killer (LAK) activity. IL-2 is a potent activator of cytolytic activity against a wide array of tumor cells, including those from fresh autologous and allogeneic tumors. Using subpopulations of lymphoid cells that were separated on Percoll density gradients, and subsequently purified by immunoadsorbance, studies were performed to examine the phenotypes of progenitor and effector cells of human LAK cells and to compare them with the phenotype of activated NK cells. From these studies, it was evident that several lymphoid subsets, including CD3+, CDw16- and CD3-, CDw16+ cells could mediate LAK lysis of fresh tumor cells. Our examination of the kinetics of activation revealed that CDw16+, NKH1+ (NK-active) cells were maximally activated by 1-2 d. In contrast, CD3+ cells appeared not to achieve maximal cytolytic activity against fresh and cultured tumor cells until days 2-3. Using limiting-dilution frequency analysis, we showed that a large percentage of cytolytically active progenitors was present among the CDw16+, NKH1+ cells. The progenitor and effector cell frequencies appear to be 10-50 times higher in these populations compared to CD3+ cells. In addition, the selective blockage by mAb to the CD3 determinant of the T cell receptor complex indicated that these two effector cell phenotypes relied on different receptors to mediate their cytotoxic activity against tumor cells. Therefore, the accumulated data suggest that there is not a single unique progenitor of LAK activity, but rather that multiple subsets of lymphocytes become cytotoxic in response to IL-2. However, the NK cell population forms the largest single component of LAK cell activity in human peripheral blood.

Antigens, Differentiation, T-Lymphocyte↗
PubMed1988

L3T4 effector cells in multiple organ-localized autoimmune disease in nude mice grafted with embryonic rat thymus.

Rat thymic grafts reconstituted T cell functions of BALB/c nude (nu/nu) mice to a considerable degree, but multiple organ-localized autoimmune diseases such as oophoritis and thyroiditis generally developed. The effector cell population in this autoimmune model was studied by adoptive transfer of the lesions into syngeneic nude mice. The transfer activity was not diminished when spleen cells were incubated with antiserum against rat cell antigen and C, but the activity was completely vanished by incubation with anti-Thy-1.2 plus C, indicating that the effector cells are T cells of mouse origin. Elimination of the L3T4+ subset virtually abolished the transfer activity, whereas that of the Lyt-2+ subset did not, indicating that the effector cells are L3T4+. Positive selection experiments by FACS also demonstrated that L3T4+ cells, but not Lyt-2+ cells, were capable of inducing the lesion, confirming the results with depletion experiments described above.

Animals↗
PubMed1997

Rapid effector function in CD8+ memory T cells.

The nature of the CD8+ T cells that underlie antiviral protective immunological memory in vivo is unclear. We have characterized peptide-specific CD8+ T lymphocytes directly ex vivo from peripheral blood in humans with past exposure to influenza virus, using single cell interferon gamma (IFN-gamma) release as a measure of effector function. In individuals in the memory state with respect to influenza virus infection, unrestimulated antigen-specific CD8+ T cells displayed IFN-gamma release within 6 h of antigen contact, identifying a population of memory CD8+ T cells that exhibit effector function without needing to divide and differentiate over several days. We have quantified circulating CD8+ effector T cells specific for six different MHC class I-restricted influenza virus epitopes. Enumeration of these CD8+ T cells gives frequencies of peptide-specific T cells that correlate with, but are in general severalfold higher than, CTL precursor frequencies derived from limiting dilution analysis, indicating that this novel population of memory CD8+ T cells has hitherto been undetected by standard means. The phenotype of these cells, which persist at a low frequency long after recovery from an acute viral infection, suggests that they play a role in protective immunological memory.

Adult↗
PubMed1997

Phenotypic and functional separation of memory and effector human CD8+ T cells.

Human CD8+ memory- and effector-type T cells are poorly defined. We show here that, next to a naive compartment, two discrete primed subpopulations can be found within the circulating human CD8+ T cell subset. First, CD45RA-CD45R0(+) cells are reminiscent of memory-type T cells in that they express elevated levels of CD95 (Fas) and the integrin family members CD11a, CD18, CD29, CD49d, and CD49e, compared to naive CD8+ T cells, and are able to secrete not only interleukin (IL) 2 but also interferon gamma, tumor necrosis factor alpha, and IL-4. This subset does not exert cytolytic activity without prior in vitro stimulation but does contain virus-specific cytotoxic T lymphocyte (CTL) precursors. A second primed population is characterized by CD45RA expression with concomitant absence of expression of the costimulatory molecules CD27 and CD28. The CD8+CD45RA+CD27- population contains T cells expressing high levels of CD11a, CD11b, CD18, and CD49d, whereas CD62L (L-selectin) is not expressed. These T cells do not secrete IL-2 or -4 but can produce IFN-gamma and TNF-alpha. In accordance with this finding, cells contained within this subpopulation depend for proliferation on exogenous growth factors such as IL-2 and -15. Interestingly, CD8+CD45RA+CD27- cells parallel effector CTLs, as they abundantly express Fas-ligand mRNA, contain perforin and granzyme B, and have high cytolytic activity without in vitro prestimulation. Based on both phenotypic and functional properties, we conclude that memory- and effector-type T cells can be separated as distinct entities within the human CD8+ T cell subset.

Adult↗
PubMed1998

Viral immune evasion due to persistence of activated T cells without effector function.

We examined the regulation of virus-specific CD8 T cell responses during chronic lymphocytic choriomeningitis virus (LCMV) infection of mice. Our study shows that within the same persistently infected host, different mechanisms can operate to silence antiviral T cell responses; CD8 T cells specific to one dominant viral epitope were deleted, whereas CD8 T cells responding to another dominant epitope persisted indefinitely. These virus-specific CD8 T cells expressed activation markers (CD69(hi), CD44(hi), CD62Llo) and proliferated in vivo but were unable to elaborate any antiviral effector functions. This unresponsive phenotype was more pronounced under conditions of CD4 T cell deficiency, highlighting the importance of CD8- CD4 T cell collaboration in controlling persistent infections. Importantly, in the presence of CD4 T cell help, adequate CD8 effector activity was maintained and the chronic viral infection eventually resolved. The persistence of activated virus-specific CD8 T cells without effector function reveals a novel mechanism for silencing antiviral immune responses and also offers new possibilities for enhancing CD8 T cell immunity in chronically infected hosts.

Animals↗
PubMed2001

Cytokine-driven proliferation and differentiation of human naive, central memory, and effector memory CD4(+) T cells.

Memory T lymphocytes proliferate in vivo in the absence of antigen maintaining a pool of central memory T cells (T(CM)) and effector memory T cells (T(EM)) with distinct effector function and homing capacity. We compared human CD4(+) naive T, T(CM), and T(EM) cells for their capacity to proliferate in response to cytokines, that have been implicated in T cell homeostasis. Interleukin (IL)-7 and IL-15 expanded with very high efficiency T(EM), while T(CM) were less responsive and naive T cells failed to respond. Dendritic cells (DCs) and DC-derived cytokines allowed naive T cells to proliferate selectively in response to IL-4, and potently boosted the response of T(CM) to IL-7 and IL-15 by increasing the expression of the IL-2/IL-15Rbeta and the common gamma chain (gamma(c)). The extracellular signal regulated kinase and the p38 mitogen-activated protein (MAP) kinases were selectively required for TCR and cytokine-driven proliferation, respectively. Importantly, in cytokine-driven cultures, some of the proliferating T(CM) differentiated to T(EM)-like cells acquiring effector function and switching chemokine receptor expression from CCR7 to CCR5. The sustained antigen-independent generation of T(EM) from a pool of T(CM) cells provides a plausible mechanism for the maintenance of a polyclonal and functionally diverse repertoire of human CD4(+) memory T cells.

CD4-Positive T-Lymphocytes↗
PubMed2001

Migratory properties of naive, effector, and memory CD8(+) T cells.

It has been proposed that two different antigen-experienced T cell subsets may be distinguishable by their preferential ability to home to lymphoid organs (central memory cells) or nonlymphoid tissues (effector memory/effector cells). We have shown recently that murine antigen-primed CD8(+) T cells cultured in interleukin (IL)-15 (CD8(IL-15)) resemble central memory cells in phenotype and function. In contrast, primed CD8(+) T cells cultured in IL-2 (CD8(IL-2)) become cytotoxic effector cells. Here, the migratory behavior of these two subsets was investigated. Naive, CD8(IL-15) cells and, to a lesser degree, CD8(IL-2) cells localized to T cell areas in the spleen, but only naive and CD8(IL-15) cells homed to lymph nodes (LNs) and Peyer's patches. Intravital microscopy of peripheral LNs revealed that CD8(IL-15) cells, but not CD8(IL-2) cells, rolled and arrested in high endothelial venules (HEVs). Migration of CD8(IL-15) cells to LNs depended on L-selectin and required chemokines that bind CC chemokine receptor (CCR)7. Both antigen-experienced populations, but not naive T cells, responded to inflammatory chemokines and accumulated at sites of inflammation. However, CD8(IL-2) cells were 12 times more efficient in migrating to inflamed peritoneum than CD8(IL-15) cells. Furthermore, CD8(IL-15) cells proliferated rapidly upon reencounter with antigen at sites of inflammation. Thus, central memory-like CD8(IL-15) cells home avidly to lymphoid organs and moderately to sites of inflammation, where they mediate rapid recall responses, whereas CD8(IL-2) effector T cells accumulate in inflamed tissues, but are excluded from most lymphoid organs.

Animals↗
PubMed2002

Uncoupling of proliferative potential and gain of effector function by CD8(+) T cells responding to self-antigens.

Professional antigen-presenting cells (APCs) are capable of transporting self-antigens from peripheral tissues to secondary lymphoid organs where they are presented to potentially autoreactive CD8(+) T cells. In the absence of an inflammatory response, this results in immune tolerance. The presence of activated, antigen-specific CD4(+) T cells converts this tolerogenic encounter into an immunogenic one by promoting extensive proliferation of CD8(+) T cells and their development into effectors. Surprisingly, activation of APCs with an agonistic antibody specific for CD40 could not substitute for CD4(+) help in this task. Anti-CD40 induced recruitment of dendritic cells expressing high levels of B7 costimulatory molecules into the lymph nodes, which in turn, greatly enhanced activation and expansion of CD8(+) T cells. However, these activated CD8(+) cells did not demonstrate effector function. We conclude that proliferative potential and gain of effector function are separable events in the differentiation program of CD8(+) T cells.

Animals↗
PubMed2003

Signal 3 determines tolerance versus full activation of naive CD8 T cells: dissociating proliferation and development of effector function.

Activation of naive CD8 T cells to undergo clonal expansion and develop effector function requires three signals: (a) Ag, (b) costimulation, and (c) IL-12 or adjuvant. The requirement for the third signal to stimulate Ag-dependent proliferation is variable, making the greatest contribution when Ag levels are low. At high Ag levels, extensive proliferation can occur in vitro or in vivo in the absence of a third signal. However, despite having undergone the same number of divisions, cells that expand in the absence of a third signal fail to develop cytolytic effector function. Thus, proliferation and development of cytolytic function can be fully uncoupled. Furthermore, these cells are rendered functionally tolerant in vivo, in that subsequent restimulation with a potent stimulus results in limited clonal expansion, impaired IFN-gamma production, and no cytolytic function. Thus, the presence or absence of the third signal appears to be a critical variable in determining whether stimulation by Ag results in tolerance versus development of effector function and establishment of a responsive memory population.

Animals↗
PubMed2005

Live imaging of effector cell trafficking and autoantigen recognition within the unfolding autoimmune encephalomyelitis lesion.

We tracked pathogenic myelin basic protein-specific CD4+ effector T cells in early central nervous system (CNS) lesions of experimental autoimmune encephalomyelitis (EAE) by combining two-photon imaging and fluorescence video microscopy. We made two key observations: (a) the majority of the cells (65%) moved fast (maximal speed 25 microm/min) and apparently nondirected through the compact tissue; and (b) a second group of effector T cells (35%) appeared tethered to a fixed point. Polarization of T cell receptor and adhesion molecules (lymphocyte function-associated antigen 1) towards this fixed point suggests the formation of immune synapses. Nonpathogenic, ovalbumin-specific T cells were not tethered in the CNS and did not form synapse-like contacts, but moved through the tissue. After intrathecal injection of antigen, 40% of ovalbumin-specific T cells became tethered. Conversely, injection of anti-major histocompatibility complex class II antibodies profoundly reduced the number of stationary pathogenic T cells within the CNS (to 15%). We propose that rapid penetration of the CNS parenchyma by numerous autoimmune effector T cells along with multiple autoantigen-presentation events are responsible for the fulminate development of clinical EAE.

Animals↗
PubMed2005

Differential contributions of central and effector memory T cells to recall responses.

Although the absolute number of memory CD8+ T cells established in the spleen following antigen encounter remains stable for many years, the relative capacity of these cells to mediate recall responses is not known. Here we used a dual adoptive transfer approach to demonstrate a progressive increase in the quality of memory T cell pools in terms of their ability to proliferate and accumulate at effector sites in response to secondary pathogen challenge. This temporal increase in efficacy occurred in CD62L lo (effector memory) and CD62L hi (central memory) subpopulations, but was most prominent in the CD62L hi subpopulation. These data indicate that the contribution of effector memory and central memory T cells to the recall response changes substantially over time.

Adoptive Transfer↗
PubMed2000

Pneumococcal capsular polysaccharide-specific IgA triggers efficient neutrophil effector functions via FcalphaRI (CD89).

Specific anti-capsular polysaccharide IgG is believed to be important for protection against infection by Streptococcus pneumoniae. Significant IgA responses have been observed after vaccination with pneumococcal vaccines, but the role of this isotype in anti-pneumococcal host defense is unclear. Here, it is shown that purified serum IgA specific for pneumococcal capsular polysaccharides can initiate efficient cellular effector functions, such as phagocytosis, via interaction with the myeloid IgA receptor, FcalphaRI (CD89). The efficiency of FcalphaR-triggered granulocyte effector functions was comparable to that of FcgammaRIIa (CD32), as shown in experiments with bispecific antibodies. These results support a role for polysaccharide-specific IgA in antipneumococcal cellular effector function and suggest that FcalphaRI represents an important leukocyte receptor for immunity against S. pneumoniae.

Antibodies, Bacterial↗
PubMed2001

Chimeric antigen receptors for the retargeting of cytotoxic effector cells.

T lymphocytes recognize specific antigens through interaction of the T cell receptor (TCR) with short peptides presented by major histocompatibility complex (MHC) class I or II molecules. For initial activation and clonal expansion, naïve T cells are dependent on professional antigen-presenting cells (APCs) that provide additional co-stimulatory signals. TCR activation in the absence of co-stimulation can result in unresponsiveness and clonal anergy. To bypass immunization, different approaches for the derivation of cytotoxic effector cells with grafted recognition specificity have been developed. Chimeric antigen receptors have been constructed that consist of binding domains derived from natural ligands or antibodies specific for cell-surface antigens, genetically fused to effector molecules such as the TCR alpha and beta chains, or components of the TCR-associated CD3 complex. Upon antigen binding, such chimeric receptors link to endogenous signaling pathways in the effector cell and generate activating signals similar to those initiated by the TCR complex. Since the first reports on chimeric antigen receptors, this concept has steadily been refined and the molecular design of chimeric receptors has been optimized. Aided by advances in recombinant antibody technology, chimeric antigen receptors targeted to a wide variety of antigens on the surface of cancer cells and of cells infected by human immunodeficiency virus (HIV) have been generated. In initial clinical studies, infusion of such cells into patients proved to be safe and transient therapeutic effects have been observed.

Animals↗
PubMed2001

Functional synergy between Rab5 effector Rabaptin-5 and exchange factor Rabex-5 when physically associated in a complex.

Rab GTPases are central elements of the vesicular transport machinery. An emerging view is that downstream effectors of these GTPases are multiprotein complexes that include nucleotide exchange factors to ensure coupling between GTPase activation and effector function. We have previously shown that Rab5, which regulates various steps of transport along the early endocytic pathway, is activated by a complex consisting of Rabex-5, a Rab5 nucleotide exchange factor, and the effector Rabaptin-5. We postulated that the physical association of these two proteins is necessary for their activity in Rab5-dependent endocytic membrane transport. To evaluate the functional implications of such complex formation, we have reconstituted it with the use of recombinant proteins and characterized its properties. First, we show that Rabaptin-5 increases the exchange activity of Rabex-5 on Rab5. Second, Rab5-dependent recruitment of Rabaptin-5 to early endosomes is completely dependent on its physical association with Rabex-5. Third, complex formation between Rabaptin-5 and Rabex-5 is essential for early endosome homotypic fusion. These results reveal a functional synergy between Rabaptin-5 and Rabex-5 in the complex and have implications for the function of analogous complexes for Rab and Rho GTPases.

Animals↗
PubMed2004

CIN85 associates with multiple effectors controlling intracellular trafficking of epidermal growth factor receptors.

CIN85 is a multidomain adaptor protein involved in Cbl-mediated down-regulation of epidermal growth factor (EGF) receptors. CIN85 src homology 3 domains specifically bind to a proline-arginine (PxxxPR) motif in Cbl, and this association seems to be important for EGF receptor endocytosis. Here, we report identification of novel CIN85 effectors, all containing one or more PxxxPR motifs, that are indispensable for their mutual interactions. These effectors include phosphatidyl-inositol phosphatases SHIP-1 and synaptojanin 2B1, Arf GTPase-activating proteins ASAP1 and ARAP3, adaptor proteins Hip1R and STAP1, and a Rho exchange factor, p115Rho GEF. Acting as a molecular scaffold, CIN85 clusters its effectors and recruits them to high-molecular-weight complexes in cytosolic extracts of cells. Further characterization of CIN85 binding to ASAP1 revealed that formation of the complex is independent on cell stimulation. Overexpression of ASAP1 increased EGF receptor recycling, whereas ASAP1 containing mutated PxxxPR motif failed to promote this event. We propose that CIN85 functions as a scaffold molecule that binds to numerous endocytic accessory proteins, thus controlling distinct steps in trafficking of EGF receptors along the endocytic and recycling pathways.

Adaptor Proteins, Signal Transducing↗
PubMed2025

Effectidor II: a pan-genomic AI-based algorithm for the prediction of type III secretion system effectors.

MOTIVATION: Type III secretion systems are used by many Gram-negative bacteria to inject type 3 effectors (T3Es) directly into eukaryotic cells, promoting disease or provoking immune response. Because of these opposing evolutionary forces, T3E repertoires often vary within taxonomic groups. Identifying the full effector gene repertoire in genomes of related individuals is crucial for determining core and specialized effectors, understanding the disease dynamics, and developing appropriate management strategies against pathogens. It can also help uncover novel T3Es that have recently emerged in a population. Our previously published Effectidor web server successfully addressed the challenge of identifying T3Es in a single bacterial genome. Here, we enriched the web server with various novel capabilities, including the identification of T3Es from multiple genome sequences simultaneously. RESULTS: We present Effectidor II, a web server that relies on machine learning to predict T3E-encoding genes within bacterial pan-genomes. We demonstrate the benefit of learning based on features extracted from the entire sequences comprising the pan-genome and report a novel T3E discovered by it in Xanthomonas euroxanthea. AVAILABILITY AND IMPLEMENTATION: Effectidor II is available at: https://effectidor.tau.ac.il and the source code is available at: https://github.com/naamawagner/Effectidor. A stand-alone version of Effectidor II is available at: https://github.com/naamawagner/Effectidor/tree/StandAlone. The source code for the standalone version and the data used in this work are also provided in https://doi.org/10.5281/zenodo.15081636.

Type III Secretion Systems↗
PubMed2000

Supramolecular structure of the Shigella type III secretion machinery: the needle part is changeable in length and essential for delivery of effectors.

We investigated the supramolecular structure of the SHIGELLA: type III secretion machinery including its major components. Our results indicated that the machinery was composed of needle and basal parts with respective lengths of 45.4 +/- 3.3 and 31.6 +/- 0.3 nm, and contained MxiD, MxiG, MxiJ and MxiH. spa47, encoding a putative F(1)-type ATPase, was required for the secretion of effector proteins via the type III system and was involved in the formation of the needle. The spa47 mutant produced a defective, needle-less type III structure, which contained MxiD, MxiG and MxiJ but not MxiH. The mxiH mutant produced a defective type III structure lacking the needle and failed to secrete effector proteins. Upon overexpression of MxiH in the mxiH mutant, the bacteria produced type III structures with protruding dramatically long needles, and showed a remarkable increase in invasiveness. Our results suggest that MxiH is the major needle component of the type III machinery and is essential for delivery of the effector proteins, and that the level of MxiH affects the length of the needle.

Adhesins, Bacterial↗
PubMed2002

Shigella deliver an effector protein to trigger host microtubule destabilization, which promotes Rac1 activity and efficient bacterial internalization.

Shigella deliver a subset of effectors into the host cell via the type III secretion system, that stimulate host cell signal pathways to modulate the actin dynamics required for invasion of epithelial cells. Here we show that one of the Shigella effectors, called VirA, can interact with tubulin to promote microtubule (MT) destabilization, and elicit protrusions of membrane ruffling. Under in vitro conditions, VirA inhibited polymerization of tubulin and stimulated MT destabilization. Upon microinjection of VirA into HeLa cells, a localized membrane ruffling was induced rapidly. Overexpression of VirA in host cells caused MT destruction and protruding membrane ruffles which were absent when VirA was co-expressed with a dominant-negative Rac1 mutant. Indeed, Shigella but not the virA mutant stimulated Rac1, including the formation of membrane ruffles in infected cells. Importantly, the MT structure beneath the protruding ruffling was destroyed. Furthermore, drug-induced MT growth in HeLa cells greatly enhanced the Shigella entry. These results indicate that VirA is a novel type of bacterial effector capable of inducing membrane ruffling through the stimulation of MT destabilization.

Actins↗