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Vgamma9Vdelta2 T lymphocytes are broadly reactive against various intracellular pathogens and display both lytic and proliferative responses to human immunodeficiency virus (HIV)-infected cells. HIV infection of peripheral blood mononuclear cell cultures led to absolute increases in Vgamma9Vdelta2 T cells accompanied by decreased p24 levels. Strong gammadelta T cell activation with nonpeptidic mycobacterial phosphoantigens (TUBAg1 extract or synthetic isopentenyl pyrophosphate) resulted in potent inhibition of HIV replication through soluble released factors. Subsequent analyses showed that phosphoantigen-activated gammadelta T cells produced substantial amounts of beta-chemokines (macrophage inflammatory protein [MIP]-1alpha, MIP-1beta, and regulated-on-activation, normal T-cell-expressed and -secreted beta-chemokine [RANTES]), which represent the natural ligand for the CCR5 HIV coreceptor. Accordingly, anti-beta-chemokine antibodies neutralized the inhibition of monocytotropic HIV strains by gammadelta T cell-released factors. Moreover, a T-tropic HIV strain using the CXCR4 coreceptor for virus entry was potently inhibited. Together, these data reveal that phosphoantigen-activated gammadelta T cells are an important source of CC chemokines and may suppress HIV replication through cell-released antiviral factors. [ABSTRACT FROM AUTHOR]

Examines the intracellular mycobacterial viability of mycobacterium tuberculosis (MTB)-induced apoptosis in monocytes. Association of MTB- induces apoptosis with CD14 expression; Correlation between MTB high doses and parasite survival; Role of monocytes on cytokines and chemokines release.

Background: Plasmodium falciparum placental infection primes the fetal immune system and alters infant immunity. Mechanisms leading to these outcomes are not completely understood. We focused on Vγ2Vδ2 cells, which are part of the immune response against many pathogens, including P. falciparum. These unconventional lymphocytes respond directly to small, nonpeptidic antigens, independent of major histocompatibility complex presentation. We wondered whether placental malaria, which may increase fetal exposure to P. falciparum metabolites, triggers a response by neonatal Vγ2Vδ2 lymphocytes that can be a marker for the extent of fetal exposure to malarial antigens., Methods: Cord blood mononuclear cells were collected from 15 neonates born to mothers with P. falciparum infection during pregnancy (8 with placental malaria) and 25 unexposed neonates. Vγ2Vδ2 cell phenotype, repertoire, and proliferative responses were compared between newborns exposed and those unexposed to P. falciparum., Results: Placental malaria-exposed neonates had increased proportions of central memory Vγ2Vδ2 cells in cord blood, with an altered Vγ2 chain repertoire ex vivo and after stimulation., Conclusion: Our results suggest that placental malaria affects the phenotype and repertoire of neonatal Vγ2Vδ2 lymphocytes. Placental malaria may lower the capacity for subsequent Vγ2Vδ2 cell responses and impair the natural resistance to infectious diseases or the response to pediatric vaccination.

Mycobacterium tuberculosis induces apoptosis in human monocyte-derived macrophages (MDMs) during the early stages of infection. We investigated the proapoptotic role of cell wall-associated mycobacterial 19-kDa lipoprotein and the possible association between 19-kDa lipoprotein signaling and production of proinflammatory cytokines. Purified mycobacterial 19-kDa lipoprotein, 19-kDa lipoprotein-expressing M. smegmatis (M. smegmatis 19+), 19-kDa lipoprotein knockout (KO) M. tuberculosis, and 19-kDa lipoprotein KO M. bovis bacille Calmette-Guerin (BCG) strains were analyzed for their ability to induce apoptosis in MDMs. The 19-kDa lipoprotein and infection with M. smegmatis 19+ induced apoptosis in MDMs. M. tuberculosis and BCG KO strains had significantly decreased abilities to induce apoptosis. The 19-kDa lipoprotein proapoptotic signal was mediated by Toll-like receptor 2 but not by tumor necrosis factor-alpha. Only the release of interleukin (IL)-1 beta was decreased after infection with 19-kDa lipoprotein KO strains. These findings indicate that the 19-kDa lipoprotein is the main signal required to trigger both apoptosis and the release of IL-1 beta during the early stages of mycobacterial infection.

Sphingosine 1-phosphate (S1P), a polar sphingolipid metabolite, is involved in a wide spectrum of biological processes, including Ca(++) mobilization, cell growth, differentiation, motility, and cytoskeleton organization. Here, we show a novel role of S1P in the induction of antimicrobial activity in human macrophages that leads to the intracellular killing of nonpathogenic Mycobacterium smegmatis and pathogenic M. tuberculosis. Such activity is mediated by host phospholipase D, which favors the acidification of mycobacteria-containing phagosomes. Moreover, when it was intravenously injected in mycobacteria-infected mice, S1P reduced mycobacterial growth and pulmonary tissue damage. These results identify S1P as a novel regulator of the host antimicrobial effector pathways.

T cells expressing Vgamma9Vdelta2 display lytic and proliferative responses against human immunodeficiency virus (HIV)-infected cells and release antiviral soluble factors. Chronic HIV-positive patients have deep changes in the composition and function of the circulating gammadelta T cell pool that are restored by highly active antiretroviral therapy (HAART). gammadelta T cells were analyzed during the rapid plasma HIV RNA rebound in HIV-infected patients undergoing structured treatment interruption (STI). A loss in circulating Vgamma9Vdelta2 T cells was observed, indicating that acute HIV replication may influence Vgamma9Vdelta2 homeostasis. These cells were lost among CD45RA(-)CD27(-) Vgamma9Vdelta2 T cell effectors, and a significant unresponsiveness, measured as antigen-driven interferon-gamma production, was observed during STI. After HAART resumption and consequent inhibition of HIV replication, Vgamma9Vdelta2 T cell reactivity was restored both quantitatively and functionally. These observations indicate that Vgamma9Vdelta2 T cells are activated early after active HIV replication but are rapidly lost when viremia is not controlled.

Better understanding of the mechanisms of proinflammatory cytokine production during human immunodeficiency virus (HIV) type 1 infection is of pivotal importance. The effect of HIV-1 infection on recombinant CD40 ligand (CD40L)-induced interleukin (IL)-1beta and IL-6 production by human macrophages was analyzed. ELISA and cytofluorometric analysis demonstrated that CD40L stimulation of HIV-1-infected macrophages resulted in substantial production of IL-1beta and IL-6. In contrast, no cytokine response was observed in uninfected cells. No modulation of the receptor for CD40 was found to account for the enhanced response to CD40L. The CD40L effect was not due to lipopolysaccharide contamination and was completely abrogated by preincubation with a monoclonal anti-CD40L antibody. mRNA studies indicated that the priming effect of HIV-1 on the macrophage response to CD40L was regulated at the transcriptional level. Finally, the effect of HIV-1 on the cytokine response could not be abolished by the HIV-1 protease inhibitor U75875 at concentrations that completely suppressed HIV-1 replication.

Mycobacterium tuberculosis and human immunodeficiency virus type 1 (HIV-1) are virulent intracellular pathogens that invade and multiply within macrophages. The effect of M. tuberculosis on HIV-1 infection and replication was analyzed in vitro using human monocyte-derived macrophages (MDM) isolated from peripheral blood mononuclear cells by countercurrent centrifugal elutriation. Preinfection of MDM with M. tuberculosis followed by HIV-1 infection resulted in an increase in p24 release, reverse transcriptase activity, and infective virus production. In contrast, no increase in HIV-1 production was observed when MDM were infected with Mycobacterium avium complex or heat-killed M. tuberculosis. Coinfected MDM were potent stimulators of T cell proliferation, while HIV-1-infected MDM failed to present exogenous tuberculin to T cells. Furthermore, coinfected MDM showed an increased capacity to transmit HIV-1 to activated T cells. These results suggest that M. tuberculosis infection can both up-regulate HIV-1 infection and replication within MDM and increase the efficiency of virus transmission from infected MDM to T cells.