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PubMed2002

Transcription of the SsrAB regulon is repressed by alkaline pH and is independent of PhoPQ and magnesium concentration.

The Salmonella pathogenicity island 2 (SPI-2) type III secretion system is expressed by intracellular bacteria and translocates effector proteins across the vacuolar membrane. Signals sensed by Salmonella enterica serovar Typhimurium in the intracellular compartment activate SPI-2 gene expression through the two-component regulatory system SsrAB. The effects of environmental and genetic signals on expression of the SsrAB-regulated gene sspH2 were examined. SsrAB-dependent activation of sspH2 was detected in the presence of both low and moderate concentrations of magnesium or calcium and at acidic and neutral pHs. The levels of expression were comparable to those detected in bacteria recovered from cultured macrophages. The induction in media at alkaline pHs (pH 7.5 and 8.0) was greatly reduced compared to the induction observed at pH 7.0 or at a lower pH, suggesting that alkaline pH represses SsrAB activation. In addition, the PhoPQ two-component system, which is also activated intracellularly, was not required for activation of SsrAB.

Bacterial Proteins↗

PubMed1991

Tumor necrosis factor-alpha: central regulatory cytokine in the induction of macrophage antimicrobial activities.

Expression of activated macrophage resistance to infection requires the cooperative interaction of interferon-gamma (IFN-gamma) and either interleukin-2 (IL-2), interleukin-4 or granulocyte/macrophage-colony-stimulating factor: no single cytokine is effective. For IFN-gamma and IL-2, the effector activity can be suppressed by the presence of anti-tumor necrosis factor-alpha (TNF-alpha) antibodies in the reaction mixture. IFN-gamma and IL-2, only in combination, induce TNF-alpha-specific mRNA and secretion of this cytokine by macrophages. Development of intracellular killing activity by activated macrophages also requires the autocrine effects of TNF-alpha. IFN-gamma provides the first signal for the production of nitric oxide (NO), the effector molecule for intracellular destruction of parasites. When IFN-gamma-treated cells are infected with pathogens, they are stimulated to make TNF-alpha. Expression of intracellular killing, as well as production of NO, is inhibited by anti-TNF-alpha antibody.

Animals↗

PubMed2006

Molecular basis for the modulation of native T-type Ca2+ channels in vivo by Ca2+/calmodulin-dependent protein kinase II.

Ang II receptor activation increases cytosolic Ca2+ levels to enhance the synthesis and secretion of aldosterone, a recently identified early pathogenic stimulus that adversely influences cardiovascular homeostasis. Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a downstream effector of the Ang II-elicited signaling cascade that serves as a key intracellular Ca2+ sensor to feedback-regulate Ca2+ entry through voltage-gated Ca2+ channels. However, the molecular mechanism(s) by which CaMKII regulates these important physiological targets to increase Ca2+ entry remain unresolved. We show here that CaMKII forms a signaling complex with alpha1H T-type Ca2+ channels, directly interacting with the intracellular loop connecting domains II and III of the channel pore (II-III loop). Activation of the kinase mediated the phosphorylation of Ser1198 in the II-III loop and the positive feedback regulation of channel gating both in intact cells in situ and in cells of the native adrenal zona glomerulosa stimulated by Ang II in vivo. These data define the molecular basis for the in vivo modulation of native T-type Ca2+ channels by CaMKII and suggest that the disruption of this signaling complex in the zona glomerulosa may provide a new therapeutic approach to limit aldosterone production and cardiovascular disease progression.

Base Sequence↗

PubMed2004

IL-8 responsiveness defines a subset of CD8 T cells poised to kill.

CD8 T cells play a key role in host defense against intracellular pathogens. Efficient migration of these cells into sites of infection is therefore intimately linked to their effector function. The molecular mechanisms that control CD8 T-cell trafficking into sites of infection and inflammation are not well understood, but the chemokine/chemokine receptor system is thought to orchestrate this process. Here we systematically examined the chemokine receptor profile expressed on human CD8 T cells. Surprisingly, we found that CXC chemokine receptor 1 (CXCR1), the predominant neutrophil chemokine receptor, defined a novel interleukin-8/CXC ligand 8 (IL-8/CXCL8)-responsive CD8 T-cell subset that was enriched in perforin, granzyme B, and interferon-gamma (IFNgamma), and had high cytotoxic potential. CXCR1 expression was down-regulated by antigen stimulation both in vitro and in vivo, suggesting antigen-dependent shaping of the migratory characteristics of CD8 T cells. On virus-specific CD8 T cells from persons with a history of Epstein-Barr virus (EBV) and influenza infection, CXCR1 expression was restricted to terminally differentiated effector memory cells. In HIV-1 infection, CXCR1-expressing HIV-1-specific CD8 T cells were present only in persons who were able to control HIV-1 replication during structured treatment interruptions. Thus, CXCR1 identifies a subset of CD8 T cells poised for immediate cytotoxicity and early recruitment into sites of innate immune system activation.

Antigens↗

PubMed2004

Direct Toll-like receptor 2 mediated co-stimulation of T cells in the mouse system as a basis for chronic inflammatory joint disease.

The pathogenesis of chronic inflammatory joint diseases such as adult and juvenile rheumatoid arthritis and Lyme arthritis is still poorly understood. Central to the various hypotheses in this respect is the notable involvement of T and B cells. Here we develop the premise that the nominal antigen-independent, polyclonal activation of preactivated T cells via Toll-like receptor (TLR)-2 has a pivotal role in the initiation and perpetuation of pathogen-induced chronic inflammatory joint disease. We support this with the following evidence. Both naive and effector T cells express TLR-2. A prototypic lipoprotein, Lip-OspA, from the etiological agent of Lyme disease, namely Borrelia burgdorferi, but not its delipidated form or lipopolysaccharide, was able to provide direct antigen-nonspecific co-stimulatory signals to both antigen-sensitized naive T cells and cytotoxic T lymphocyte (CTL) lines via TLR-2. Lip-OspA induced the proliferation and interferon (IFN)-gamma secretion of purified, anti-CD3-sensitized, naive T cells from C57BL/6 mice but not from TLR-2-deficient mice. Induction of proliferation and IFN-gamma secretion of CTL lines by Lip-OspA was independent of T cell receptor (TCR) engagement but was considerably enhanced after suboptimal TCR activation and was inhibitable by monoclonal antibodies against TLR-2.

Animals↗

PubMed2003

Human NKT cells express granulysin and exhibit antimycobacterial activity.

Human NKT cells are a unique subset of T cells that express an invariant V alpha 24 TCR that recognizes the nonclassical Ag-presenting molecule CD1d. Activation of NKT cells is greatly augmented by the marine sponge-derived glycolipid alpha-galactosylceramide (alpha GalCer). Because human monocyte-derived cells express CD1d and can harbor the intracellular pathogen Mycobacterium tuberculosis, we asked whether the addition of alpha GalCer could be used to induce effector functions of NKT cells against infected monocytes, macrophages, and monocyte-derived dendritic cells. NKT cells secreted IFN-gamma, proliferated, and exerted lytic activity in response to alpha GalCer-pulsed monocyte-derived cells. Importantly, alpha GalCer-activated NKT cells restricted the growth of intracellular M. tuberculosis in a CD1d-dependent manner. NKT cells that exhibited antimycobacterial activity also expressed granulysin, an antimicrobial peptide shown to mediate an antimycobacterial activity through perturbation of the mycobacterial surface. Degranulation of NKT cells resulted in depletion of granulysin and abrogation of antimycobacterial activity. The detection of CD1d in granulomas of tuberculosis patients supports the potential interaction of NKT cells with CD1d-expressing cells at the site of disease activity. These studies provide evidence that alpha Gal Cer-activated CD1d-restricted T cells can participate in human host defense against M. tuberculosis infection.

Adjuvants, Immunologic↗

PubMed1999

Effect of fever-like whole-body hyperthermia on lymphocyte spectrin distribution, protein kinase C activity, and uropod formation.

Regional inflammation and systemic fever are hallmarks of host immune responses to pathogenic stimuli. Although the thermal element of fever is thought to enhance the activity of immune effector cells, it is unclear what the precise role of increased body temperatures is on the activation state and effector functions of lymphocytes. We report here that mild, fever-like whole body hyperthermia (WBH) treatment of mice results in a distinct increase in the numbers of tissue lymphocytes with polarized spectrin cytoskeletons and uropods, as visualized in situ. WBH also induces a coincident reorganization of protein kinase C (PKC) isozymes and increased PKC activity within T cells. These hyperthermia-induced cellular alterations are nearly identical with the previously described effects of Ag- and mitogen-induced activation on lymphocyte spectrin and PKC. Immunoprecipitation studies combined with dual staining and protein overlay assays confirmed the association of PKC beta and PKC theta with spectrin following its reorganization. The receptor for activated C kinase-1 was also found to associate with the spectrin-based cytoskeleton. Furthermore, all these molecules (spectrin, PKC beta, PKC theta, and receptor for activated C kinase-1) cotranslocate to the uropod. Enhanced intracellular spectrin phosphorylation upon WBH treatment of lymphocytes was also found and could be blocked by the PKC inhibitor bisindolylmaleimide I (GF109203X). These data suggest that the thermal element of fever, as mimicked by these studies, can modulate critical steps in the signal transduction pathways necessary for effective lymphocyte activation and function. Further work is needed to determine the cellular target(s) that transduces the signaling pathway(s) induced by hyperthermia.

Animals↗

PubMed2005

Coordinate expression of CC chemokine ligand 5, granulysin, and perforin in CD8+ T cells provides a host defense mechanism against Mycobacterium tuberculosis.

The ability of CD8+ T cells to kill intracellular pathogens depends upon their capacity to attract infected cells as well as their secretion of cytolytic and antimicrobial effector molecules. We examined the Ag-induced expression of three immune effector molecules contained within cytoplasmic granules of human CD8+ T cells: the chemokine CCL5, the cytolytic molecule perforin, and the antimicrobial protein granulysin. Macrophages infected with virulent Mycobacterium tuberculosis triggered the expression of CCL5 in CD8+ T cells only in donors with previous exposure to the tuberculosis bacteria, not in naive donors. Functionally, CCL5 efficiently attracted M. tuberculosis-infected macrophages, but failed to exert direct antibacterial activity. Infected macrophages also triggered the expression of granulysin in CD8+ T cells, and granulysin was found to be highly active against drug-susceptible and drug-resistant M. tuberculosis clinical isolates. The vast majority of CCL5-positive cells coexpressed granulysin and perforin. Taken together, this report provides evidence that a subset of CD8+ T cells coordinately expresses CCL5, perforin and granulysin, thereby providing a host mechanism to attract M. tuberculosis-infected macrophages and kill the intracellular pathogen.

Animals↗

PubMed1999

[Pathogenesis of pneumocystis carinii pneumonia].

Pneumocystis carinii is a ubiquitous fungus and opportunistic resident of the bronchoalveolar lumen of men and a variety of other mammalian species. This microorganism replicates under immunosuppressive conditions, ultimately resulting in lethal pneumonia (PcP) if left untreated. In the past decade, considerable progress has been made concerning the understanding of the underlying pathogenic mechanisms of this infection, mostly with the help of animal models such as SCID (severe combined immunodeficiency) or gene-knock-out mice. Partially conflicting data derived from animal studies lead to the assumption that there is no single relevant model for PcP. The T cell-mediated branch of the immune system is recognised as the major component in the host's ability to resist or overcome an infection with P. carinii. Natural, nonspecific immune mechanisms involving mononuclear phagocytes and elaborating a variety of cytokines and other immunomediators play an important role in initiating the immunoresponse as well as in its effector phase, but it is the CD4+ T lymphocytes which are essential for coordinating the complete eradication of this pathogen. The biological function and immunological effects of antigens expressed on the surface of or secreted by P. carinii organisms is not yet fully known. Hopefully, characterisation of these molecules, clarification of their immunological properties and the evaluation of the interactions between humoral and cellular as well as specific and nonspecific parts of the immune system will lead to new insights into the pathogenesis of P. carinii pneumonia.

Animals↗

PubMedDate not supplied

Mechanisms of autoimmunity and AIDS: prospects for therapeutic intervention.

The network theory of autoimmunity is presented with recent experimental data relevant to the understanding of the pathogenesis of AIDS. Schematically, effector T cells specific for self-antigens exist normally, but their activity is modulated and prevented by networks of regulatory T cells. As a result of mimicry between molecular components of microorganisms and self-antigens, autoimmune disease can be triggered by specific foreign pathogens which alter the state of activity of the network from suppression to activation. Conversely, by a procedure known as T-cell vaccination, autologous effector T cells re-injected after in vitro stimulation and attenuation may alter the state of the network from an activation to a suppression. Numerous observations are reviewed that support the concept of autoimmune activity in the destruction of non-infected T4 cells. Such activity is presumed to be triggered by an antigen of viral origin, the most likely, but not the only one, being the envelope protein gp 120. Based on this hypothesis, a T-cell vaccination procedure against effector T cells responsible for autoimmunopathic activity in HIV-seropositive patients is proposed, similar to the one known from experimental study of autoimmunity and presently being tested in human autoimmune diseases. Its purpose would be to prevent T-cell loss and the onset of immunodeficiency disease in HIV-seropositive patients. Apart from its potential therapeutic value, this procedure will have use as a therapeutic test from which insight will be gained about the immunopathogenesis of AIDS.

Acquired Immunodeficiency Syndrome↗

PubMed2000

Identification and characterization of the antigen presenting cell in rat autoimmune myocarditis: evidence of bone marrow derivation and non-requirement for MHC class I compatibility with pathogenic T cells.

In the rat, autoimmune myocarditis can be produced by the infusion of activated myosin peptide specific, CD4(+), class II restricted, effector T cells. Whether antigen presenting cells (APCs), which interact with these effector T cells in the heart, are a fixed population of cells (resident dendritic, macrophage, or endothelial cells), or a dynamic bone marrow derived population has not yet been demonstrated in vivo. To study this question, bone marrow chimeras were generated using inbred Brown Norway (BN) rats, which are resistant to autoimmune myocarditis, and transplanting them after lethal irradiation with (LewisxBN) F1 bone marrow. BN rats differ at both MHC loci from the susceptible inbred Lewis rats. Two months after bone marrow transplantation, chimeric animals received Lewis T cells specific for a myocarditogenic peptide antigen. To characterize the cardiac APCs, immunohistochemistry using a battery of antibodies including Lewis-specific and broadly reactive antibodies for both MHC class I and class II, was performed on chimeric hearts, with and without infused Lewis T cells, and non-transplanted BN control hearts.All chimeric rats infused with allogeneic (Lewis), anti-cardiac myosin peptide effector T cells displayed the lesions of myocarditis. Myocarditis was not present in non-transplanted BN controls given either Lewis or F1 derived myocarditogenic T cells, nor in chimeric animals which did not receive myocarditogenic T cells, thus excluding graft vs host disease as the explanation for the inflammation in chimeric hearts with myocarditis. Marrow derived cells expressing both Lewis class I and class II MHC molecules were demonstrated on perivascular cells in the myocardium of all chimeric animals, and on infiltrating cells in chimeric animals with myocarditis. Cells expressing Lewis-specific MHC antigens were not detected in the non-transplanted BN controls. Furthermore, immunohistochemistry using broadly reactive antibodies demonstrated MHC class II on perivascular cells with a dendritic morphology in all hearts but not on endothelial cells or cardiac myocytes. These results support the hypothesis that in vivo, cardiac APCs which result in MHC class II restricted, T cell induced myocarditis are a dynamic bone marrow derived population and not a fixed population. In order to address the potential requirement of MHC class I for the initiation of autoimmune myocarditis, myocarditogenic T cells derived from either Lewis or DA(RP) rats were infused into a member of the other strain. These strains share common MHC class II genes but differ at the MHC class I loci. Myocarditis identical to that produced in the syngeneic animal was successfully transferred by the MHC class I mismatched T cells, but only after the recipient animal's native immune system was mildly suppressed. These results further support the primary role for professional antigen presentation via MHC class II restriction to the effector T cells at the initiation of autoimmune myocarditis in the heart.Together, these experiments confirm that activated effector T cells, in order to produce myocarditis, require MHC class II compatible APCs in the heart, that these APCs are bone marrow derived, and will endogenously take up and present local antigens in the target organ after bone marrow reconstitution.

Adoptive Transfer↗

PubMed2004

Can we really learn from model pathogens?

Cytolytic T (Tc) lymphocytes are the first order response of the adaptive immune system in the recovery from primary viral infections. These effector cells execute their function either by direct cytotoxicity through the Fas or perforin pathway and/or by the release of cytokines that either directly or indirectly exert antiviral activity. Mice respond to infection by closely related viruses with a vigorous Tc response, which is characterized by extensive crossreactivity on target cells infected with these viruses. However, the action of these cells can be beneficial, detrimental or neutral. From our current state of knowledge, no generalizations as to protective or detrimental effects of cytolytic effector functions in recovery from virus infections can be made. Thus, virus-host immune interactions have to be assessed individually and cannot be generalized.

Animals↗

PubMed2006

Measurement of effector protein injection by type III and type IV secretion systems by using a 13-residue phosphorylatable glycogen synthase kinase tag.

Numerous bacterial pathogens use type III secretion systems (T3SSs) or T4SSs to inject or translocate virulence proteins into eukaryotic cells. Several different reporter systems have been developed to measure the translocation of these proteins. In this study, a peptide tag-based reporter system was developed and used to monitor the injection of T3S and T4S substrates. The glycogen synthase kinase (GSK) tag is a 13-residue phosphorylatable peptide tag derived from the human GSK-3beta kinase. Translocation of a GSK-tagged protein into a eukaryotic cell results in host cell protein kinase-dependent phosphorylation of the tag, which can be detected with phosphospecific GSK-3beta antibodies. A series of expression plasmids encoding Yop-GSK fusion proteins were constructed to evaluate the ability of the GSK tag to measure the injection of Yops by the Yersinia pestis T3SS. GSK-tagged YopE, YopH, LcrQ, YopK, YopN, and YopJ were efficiently phosphorylated when translocated into HeLa cells. Similarly, the injection of GSK-CagA by the Helicobacter pylori T4SS into different cell types was measured via phosphorylation of the GSK tag. The GSK tag provides a simple method to monitor the translocation of T3S and T4S substrates.

Amino Acid Sequence↗

PubMed1999

Visualization, fate, and pathogenicity of antigen-specific CD8+ T cells in the graft-versus-host reaction.

To follow the fate of alloreactive T cell effectors in graft-vs-host disease, Ld-specific CD8+ T cells from C57BL/6 2C TCR-transgenic donors were transplanted into sublethally irradiated (750 cGy) Ld+ or Ld- recipients. In Ld- C57BL/6 or (BALB/c-dm2 x C57BL/6)F1 recipients, naive 2C T cells engrafted and survived long term, but did not acquire effector function. In Ld+ (BALB/c x C57BL/6)F1 recipients, 2C T cells engrafted, expanded, became cytolytic, destroyed host B cells and double-positive thymocytes, and later disappeared. Despite marked damage to lymphoid and hemopoietic cells by 2C T cells, no significant pathology was detected in other organs, and recipients survived. Ld+ (BALB/c x C57BL/6)F1 recipients died when LPS/endotoxin was administered on day 7 after cell transfer, while Ld- (BALB/c-dm2 x C57BL/6)F1 recipients survived. Our findings show that under certain conditions, a CD8+ T cell population recognizing an extremely limited repertoire of Ags can initiate graft-vs-host disease.

Animals↗

PubMed2001

Role of phosphatidylinositol 3-kinase and Rab5 effectors in phagosomal biogenesis and mycobacterial phagosome maturation arrest.

Phagosomal biogenesis is a fundamental biological process of particular significance for the function of phagocytic and antigen-presenting cells. The precise mechanisms governing maturation of phagosomes into phagolysosomes are not completely understood. Here, we applied the property of pathogenic mycobacteria to cause phagosome maturation arrest in infected macrophages as a tool to dissect critical steps in phagosomal biogenesis. We report the requirement for 3-phosphoinositides and acquisition of Rab5 effector early endosome autoantigen (EEA1) as essential molecular events necessary for phagosomal maturation. Unlike the model phagosomes containing latex beads, which transiently recruited EEA1, mycobacterial phagosomes excluded this regulator of vesicular trafficking that controls membrane tethering and fusion processes within the endosomal pathway and is recruited to endosomal membranes via binding to phosphatidylinositol 3-phosphate (PtdIns[3]P). Inhibitors of phosphatidylinositol 3'(OH)-kinase (PI-3K) activity diminished EEA1 recruitment to newly formed latex bead phagosomes and blocked phagosomal acquisition of late endocytic properties, indicating that generation of PtdIns(3)P plays a role in phagosomal maturation. Microinjection into macrophages of antibodies against EEA1 and the PI-3K hVPS34 reduced acquisition of late endocytic markers by latex bead phagosomes, demonstrating an essential role of these Rab5 effectors in phagosomal biogenesis. The mechanism of EEA1 exclusion from mycobacterial phagosomes was investigated using mycobacterial products. Coating of latex beads with the major mycobacterial cell envelope glycosylated phosphatidylinositol lipoarabinomannan isolated from the virulent Mycobacterium tuberculosis H37Rv, inhibited recruitment of EEA1 to latex bead phagosomes, and diminished their maturation. These findings define the generation of phosphatidylinositol 3-phosphate and EEA1 recruitment as: (a) important regulatory events in phagosomal maturation and (b) critical molecular targets affected by M. tuberculosis. This study also identifies mycobacterial phosphoinositides as products with specialized toxic properties, interfering with discrete trafficking stages in phagosomal maturation.

Androstadienes↗

PubMed1996

Effector mechanisms in demyelinating neuropathies.

While the cause of the immune-mediated neuropathies (Guillain-Barr-e syndrome, GBS; CIDP; multi-focal motor neuropathy and paraproteinemic neuropathies) remains elusive considerable progress has been made in delineating the effector mechanisms that underlie myelin destruction. In GBS circulating antibodies to glycolipids possibly precipitated by an antecedent Campylobacter jejuni infection can be detected with high frequency. These antibodies may interfere with neuromuscular transmission and eventuate myelin damage by activating the complement system, providing for the generation of chemotactically active split products C3a and C5a, the opsonin C3b, and assembly of the membrane attack complex. Such antibodies may also, via binding to the Fc receptor, target macrophages to the myelin sheath. Corroborative evidence for a crucial pathogenic role of antibody-mediated complement activation is also available for the MAG-associated neuropathies. Macrophages as decisive effector cells of myelin damage may also act by releasing injurious molecules such as oxygen radicals, nitric oxide metabolites, proteases, eicosanoids and cytokines. Demyelinative as well as degenerative actions have been described for the cytokines TNF-alpha and lymphotoxin. Increased understanding of the effector mechanisms underlying demyelination may aid in developing more efficacious treatments for this group of neuropathies.

Autoantibodies↗

PubMedDate not supplied

[The pathogenic role of inflammation in multiple sclerosis].

INTRODUCTION: Multiple sclerosis (MS) is characterized by the presence in the central nervous system (CNS) of perivascular inflammatory infiltrates containing auto-reactive T and B cells and activated macrophages thus indicating that MS is a T cell-mediated CNS-confined chronic inflammatory demyelinating disease in which the ultimate effector cell is the activated macrophage. DEVELOPMENT: The inflammatory process, leading to patchy demyelination and axonal loss, is mainly sustained by pro-inflammatory cytokines that modulate at different levels the pathogenic process underlying MS. Cytokines can 1. Sustain the 'putative' CNS-confined inflammatory process leading to the development of myelin-specific T cells; 2. Activate circulating myelin-specific T cells and shape their repertoire (Th1 versus Th2 pattern); 3. Induce the CNS recruitment of non antigen specific T cells and myelinotoxic effector cells (monocyte/macrophages) from the periphery, and 4. Cause direct oligodendrotoxicity (TNF alpha) or induce the secretion of myelinotoxic substances. The present chapter will focus on the mechanisms sustaining the activity of pro-inflammatory cytokines in MS pathogenesis.

Brain↗

PubMed2006

Induction of a virus-specific effector-memory CD4+ T cell response by attenuated SIV infection.

We investigated simian immunodeficiency virus (SIV)-specific CD4+ T cell responses in rhesus macaques chronically infected with attenuated or pathogenic SIV strains. Analysis of SIVDeltanef-infected animals revealed a relatively high frequency of SIV-specific CD4+ T cells representing 4-10% of all CD4+ T lymphocytes directed against multiple SIV proteins. Gag-specific CD4+ T cells in wild-type SIV-infected animals were 5-10-fold lower in frequency and inversely correlated with the level of plasma viremia. SIV-specific CD4+ cells from SIVDeltanef animals were predominantly CD27-CD28-CD45RAlowCCR7-CCR5-, consistent with an effector-memory subset, and included a fully differentiated CD45RA+CCR7- subpopulation. In contrast, SIV-specific CD4+ T cells from SIV-infected animals were mostly CD27+CD28+CD45RA-CCR7+CCR5+, consistent with an early central memory phenotype. The CD45RA+CCR7-CD4+ subset from SIVDeltanef animals was highly enriched for effector CD4+ T cells, as indicated by the perforin expression and up-regulation of the lysosomal membrane protein CD107a after SIV Gag stimulation. SIV-specific CD4+ T cells in attenuated SIV-infected animals were increased in frequency in bronchioalveolar lavage and decreased in lymph nodes, consistent with an effector-memory T cell population. The ability of SIVDeltanef to induce a high frequency virus-specific CD4+ T cell response with direct effector function may play a key role in protective immunity produced by vaccination with attenuated SIV strains.

Animals↗