ABSTRACT
The female genital tract (FGT) mucosa is a critically important site for immune defense against microbes. Mucosal-associated invariant T (MAIT) cells are an innate-like T-cell population that recognizes microbial riboflavin metabolite antigens in an MR1-dependent manner. The role of MAIT cells in the FGT mucosa is unknown. Here, we found that MAIT cells and MR1+ antigen-presenting cells were present in the upper and lower FGT, with distinct tissue localization of MAIT cells in endometrium vs. cervix. The MAIT cells from the FGT and blood displayed a distinct phenotype with expression of interleukin (IL)-18Rα, CD127, α4ß7, PD-1, as well as the transcription factors promyelocytic leukemia zinc finger (PLZF), RORγt, Helios, Eomes, and T-bet. Their expression levels of PLZF and Eomes were lower in the FGT compared with blood. When stimulated with Escherichia coli, MAIT cells from the FGT displayed a bias towards IL-17 and IL-22 expression, whereas blood MAIT cells produced primarily IFN-γ, TNF, and Granzyme B. Furthermore, both FGT- and blood-derived MAIT cells were polyfunctional and contributed to the T-cell-mediated response to E. coli. Thus, MAIT cells in the genital mucosa have a distinct IL-17/IL-22 profile and may have an important role in the immunological homeostasis and control of microbes at this site.
Subject(s)
Antigens, Bacterial/immunology , Cervix Uteri/immunology , Endometrium/immunology , Escherichia coli/immunology , Immunity, Innate , Mucous Membrane/immunology , Natural Killer T-Cells/immunology , Adult , Cells, Cultured , Cervix Uteri/pathology , Endometrium/pathology , Female , Histocompatibility Antigens Class I/metabolism , Humans , Interleukin-17/metabolism , Interleukin-7 Receptor alpha Subunit/metabolism , Interleukins/metabolism , Middle Aged , Minor Histocompatibility Antigens/metabolism , Nuclear Receptor Subfamily 1, Group F, Member 3/genetics , Nuclear Receptor Subfamily 1, Group F, Member 3/metabolism , Riboflavin/immunology , Interleukin-22ABSTRACT
BACKGROUND: There are strong theoretical arguments for initiating antiretroviral therapy (ART) during primary HIV-1 infection (PHI) to preserve HIV-1-specific T-cell responses and to decrease immune activation. METHODS: We assessed the degree of immune activation during PHI and after analytical treatment interruption (ATI) in plasma samples from 22 subjects by measuring 13 cytokines/chemokines with the Luminex system. Subjects initiated quadruple ART at PHI (the QUEST cohort) and were classified as responders or nonresponders according to their HIV-1 viral load (VL) 6 months post-ATI. RESULTS: During PHI, nonresponders had higher levels of HIV-1 RNA, interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-10 and eotaxin than responders (P
Subject(s)
CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Cytokines/immunology , HIV Infections/immunology , HIV-1/immunology , Antiretroviral Therapy, Highly Active/methods , CD4 Lymphocyte Count , Female , HIV Infections/drug therapy , Humans , Immunologic Factors/immunology , Male , Middle Aged , Viral Load , Withholding TreatmentABSTRACT
We have examined the role of alpha and beta chemokines in the promotion of the ontogenetic development of the brain. RANTES was expressed preferentially in human fetal astrocytes in an age-dependent manner. Astrocytes from 5-week-old brains showed high proliferation and reduced survival, whereas 10-week-old astrocytes exhibited opposite effects. These effects were suppressed by anti-RANTES or anti-RANTES receptor antibodies and were enhanced by recombinant RANTES. RANTES induced tyrosine phosphorylation of several cellular proteins and nuclear translocation of STAT-1 in astrocytes. Interferon-gamma (IFN-gamma) was required for RANTES effects because RANTES induced IFN-gamma and only 10-week-old astrocytes expressed the IFN-gamma receptor. Blocking of IFN-gamma with antibody reversed the effects of RANTES, indicating that cytokine/chemokine networks are critically involved in brain development.
Subject(s)
Astrocytes/physiology , Chemokine CCL5/metabolism , Interferon-gamma/metabolism , Interleukin-8/metabolism , Prosencephalon/embryology , Animals , Astrocytes/cytology , Cell Cycle/physiology , Cell Survival , Cells, Cultured , Chemokine CCL5/genetics , DNA-Binding Proteins/metabolism , Embryo, Mammalian/cytology , Female , Humans , Immunoblotting , Immunohistochemistry , In Situ Hybridization , Interleukin-8/genetics , Mice , Mice, Inbred C57BL , Phosphorylation , Pregnancy , Pregnancy Trimester, First , Prosencephalon/cytology , Prosencephalon/metabolism , RNA, Messenger/metabolism , Receptors, CCR5/metabolism , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , STAT1 Transcription Factor , Trans-Activators/metabolismABSTRACT
Enterococcus faecium has six penicillin-binding proteins (PBP), where PBP5 seems to be the main target for beta-lactam antibiotics. The PBP profiles of three imipenem-resistant, ampicillin-sensitive E. faecium strains, isolated from the same patient, were studied using biotinylated ampicillin and chemiluminescence detection. Imipenem resistance in these strains was found to be associated with hyperproduction of PBP5 compared to the ampicillin- and imipenem-susceptible strain ATCC 19434. PBP5 in the imipenem-resistant strains (S1, B2) exhibited a selectively decreased affinity for imipenem. An 854 bp DNA fragment, corresponding to the penicillin-binding domain of pbp5fm, was studied in the resistant strains and the reference strain. Four amino acid substitutions were observed in the resistant strains compared to the susceptible one. The contribution of these substitutions to the increased production of PBP5 in these strains is unclear since the substitution was observed also in a strain without increased production of PBP5. Our results suggest that the moderate imipenem resistance observed in these strains is associated with increased production of PBP5 with relatively decreased affinity for imipenem, and that evolution of imipenem resistance in E. faecium is dinstinct from that of the other beta-lactams such as ampicillin.
