CCR6-dependent recruitment of blood phagocytes is necessary for rapid CD4 T cell responses to local bacterial infection.
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ABSTRACT:
SUBMITTER: Ravindran R
PROVIDER: S-EPMC1907313 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:There is limited knowledge on the identity of primary CD4(+) T cell subsets selectively targeted by HIV-1 in vivo. In this study, we established a link between HIV permissiveness, phenotype/homing potential, and lineage commitment in primary CD4(+) T cells. CCR4(+)CCR6(+), CCR4(+)CCR6(-), CXCR3(+)CCR6(+), and CXCR3(+)CCR6(-) T cells expressed cytokines and transcription factors specific for Th17, Th2, Th1Th17, and Th1 lineages, respectively. CCR4(+)CCR6(+) and CXCR3(+)CCR6(+) T cells expressed the HIV coreceptors CCR5 and CXCR4 and were permissive to R5 and X4 HIV replication. CCR4(+)CCR6(-) T cells expressed CXCR4 but not CCR5 and were permissive to X4 HIV only. CXCR3(+)CCR6(-) T cells expressed CCR5 and CXCR4 but were relatively resistant to R5 and X4 HIV in vitro. Total CCR6(+) T cells compared with CCR6(-) T cells harbored higher levels of integrated HIV DNA in treatment-naive HIV-infected subjects. The frequency of total CCR6(+) T cells and those of CCR4(+)CCR6(+) and CXCR3(+)CCR6(+) T cells were diminished in chronically infected HIV-positive subjects, despite viral-suppressive therapy. A high-throughput analysis of cytokine profiles identified CXCR3(+)CCR6(+) T cells as a major source of TNF-alpha and CCL20 and demonstrated a decreased TNF-alpha/IL-10 ratio in CXCR3(+)CCR6(-) T cells. Finally, CCR4(+)CCR6(+) and CXCR3(+)CCR6(+) T cells exhibited gut- and lymph node-homing potential. Thus, we identified CCR4(+)CCR6(+) and CXCR3(+)CCR6(+) T cells as highly permissive to HIV replication, with potential to infiltrate and recruit more CCR6(+) T cells into anatomic sites of viral replication. It is necessary that new therapeutic strategies against HIV interfere with viral replication/persistence in discrete CCR6(+) T cell subsets.
| S-EPMC4321756 | biostudies-literature
Project description:The objective of this article is to investigate the contribution of colon and blood CD4 T-cell subsets expressing the chemokine receptor CCR6 to HIV persistence during antiretroviral therapy.Matched sigmoid biopsies and blood samples (n?=?13) as well as leukapheresis (n?=?20) were collected from chronically HIV-infected individuals receiving antiretroviral therapy. Subsets of CD4 T cells with distinct differentiation/polarization profiles were identified using surface markers as follows: memory (TM, CD45RA), central memory (TCM; CD45RACCR7), effector (TEM/TM; CD45RACCR7), Th17 (CCR6CCR4), Th1Th17 (CCR6CXCR3), Th1 (CCR6CXCR3), and Th2 (CCR6CCR4).We used polychromatic flow cytometry for cell sorting, nested real-time PCR for HIV DNA quantification, ELISA and flow cytometry for HIV p24 quantification. HIV reactivation was induced by TCR triggering in the presence/absence of all-trans retinoic acid.Compared with blood, the frequency of CCR6 TM was higher in the colon. In both colon and blood compartments, CCR6 TM were significantly enriched in HIV DNA when compared with their CCR6 counterparts (n?=?13). In blood, integrated HIV DNA levels were significantly enriched in CCR6 versus CCR6 TCM of four of five individuals and CCR6 versus CCR6 TEM of three of five individuals. Among blood TCM, Th17 and Th1Th17 contributed the most to the pool of cells harboring integrated HIV DNA despite their reduced frequency compared with Th2, which were infected the least. HIV reactivation was induced by TCR triggering and/or retinoic acid exposure at higher levels in CCR6 versus CCR6 TM, TCM, and TEM.CCR6 is a marker for colon and blood CD4 T cells enriched for replication-competent HIV DNA. Novel eradication strategies should target HIV persistence in CCR6CD4 T cells from various anatomic sites.
| S-EPMC5131694 | biostudies-literature
Project description:Toll-like receptors (TLRs) can recognize microbial patterns and utilize adaptor molecules, such as-MyD88 or (TRIF TIR-domain-containing adapter-inducing interferon-β), to initiate downstream signaling that ultimately affects the initiation of adaptive immunity. In addition to this inflammatory role, TLR5 expression on dendritic cells can favor antigen presentation of flagellin peptides and thus increase the sensitivity of flagellin-specific T-cell responses in vitro and in vivo. Here, we examined the role of alternative signaling pathways that might regulate flagellin antigen presentation in addition to MyD88. These studies suggest a requirement for spleen tyrosine kinase, a noncanonical TLR-signaling adaptor molecule, and its downstream molecule CARD9 in regulating the sensitivity of flagellin-specific CD4(+) T-cell responses in vitro and in vivo. Thus, a previously unappreciated signaling pathway plays an important role in regulating the dominance of flagellin-specific T-cell responses.
| S-EPMC4324162 | biostudies-literature
Project description:BackgroundThe century-old Mycobacterium bovis Bacillus Calmette-Guerin (BCG) remains the only licensed vaccine against tuberculosis (TB). Despite this, there is still a lot to learn about the immune response induced by BCG, both in terms of phenotype and specificity.MethodsWe investigated immune responses in adult individuals pre and 8 months post BCG vaccination. We specifically determined changes in gene expression, cell subset composition, DNA methylome, and the TCR repertoire induced in PBMCs and CD4 memory T cells associated with antigen stimulation by either BCG or a Mycobacterium tuberculosis (Mtb)-derived peptide pool.FindingsFollowing BCG vaccination, we observed increased frequencies of CCR6+ CD4 T cells, which includes both Th1* (CXCR3+CCR6+) and Th17 subsets, and mucosal associated invariant T cells (MAITs). A large number of immune response genes and pathways were upregulated post BCG vaccination with similar patterns observed in both PBMCs and memory CD4 T cells, thus suggesting a substantial role for CD4 T cells in the cellular response to BCG. These upregulated genes and associated pathways were also reflected in the DNA methylome. We described both qualitative and quantitative changes in the BCG-specific TCR repertoire post vaccination, and importantly found evidence for similar TCR repertoires across different subjects.InterpretationThe immune signatures defined herein can be used to track and further characterize immune responses induced by BCG, and can serve as reference for benchmarking novel vaccination strategies.
| S-EPMC8671872 | biostudies-literature
Project description:This study examines the extent to which memory CD4+ T cells share immunosurveillance strategies with CD8+ resident memory T cells (TRM). After acute viral infection, memory CD4+ T cells predominantly used residence to survey nonlymphoid tissues, albeit not as stringently as observed for CD8+ T cells. In contrast, memory CD4+ T cells were more likely to be resident within lymphoid organs than CD8+ T cells. Migration properties of memory-phenotype CD4+ T cells in non-SPF parabionts were similar, generalizing these results to diverse infections and conditions. CD4+ and CD8+ TRM shared overlapping transcriptional signatures and location-specific features, such as granzyme B expression in the small intestine, revealing tissue-specific and migration property-specific, in addition to lineage-specific, differentiation programs. Functionally, mucosal CD4+ TRM reactivation locally triggered both chemokine expression and broad immune cell activation. Thus, residence provides a dominant mechanism for regionalizing CD4+ T cell immunity, and location enforces shared transcriptional, phenotypic, and functional properties with CD8+ T cells.
| S-EPMC6504216 | biostudies-literature
Project description:Antiretroviral therapy (ART) has the potency of suppressing systemic viral replication and spread. Still, persistent human immunodeficiency virus type-1 (HIV) survive for decades during treatment in latently infected cells, making up the latent viral reservoir. This reservoir is believed to reside in subtypes of memory T cells and cell from monocytic lineages, but some functional and naïve T cells have also shown to carry latent HIV. Eradication of latently infected cells, in terms of a sterilizing cure, have proven to be a hurdle since there is a heterogeneity in mechanisms governing latency and integration site into the genome. Over the course of suppressive therapy, persisting HIV, sustained by low levels of viral replication, homeostatic proliferation, and cell to cell transmission, is a driver of chronic immune activation in the body. For the immune system to elicit an appropriate inflammatory response it is dependent on secretion of inflammatory molecules, such as chemokines and cytokines. Most chemokines are pro-inflammatory factors that facilitate leukocyte recruitment to site of inflammation where they can exert their regulatory role in response to pathological and physiological stressors e.g., infection, inflammation, and tissue damage. Alterations in chemokine receptor expression and chemokine levels modulates the activity of the immune response and in HIV infection contribute to chronic inflammation and mortality. Therefore, people living with HIV on suppressive therapy (PLWH) are at higher risk of age associated co-morbidities due to elevated immune activation and chronic inflammation induced by ART toxicities, microbiome dysbiosis leading to microbial translocation and dysregulated immune cell activation and function. As a result, the causative HIV pathogenesis and immune dysfunction further chronic immune activation. This result in a vicious cycle as immune activation is driver of HIV disease progression and inflammaeging leading to earlier onset of age-related diseases. An alternative approach in cure strategies is a functional cure for HIV aiming at suppressing viral replication without ART. A model for functional cure studies are elite controllers (EC). EC constitute a small fraction of HIV+ individuals (<0.5%) exhibiting the unique characteristic of natural control of viral replication in absence of ART. However, there is a population-based heterogeneity of how these individuals naturally supress viral replication. This heterogeneity is caused by viral genetic factors, variability of integration site in the human genome, together with host response against the pathogen and immunological factors. In terms of immune cell activation, studies have shown how EC maintain lower levels of inflammatory markers compared to PLWH. Contradictory, some studies have shown elevated inflammatory markers in EC which could be attributed to the heterogeneity of the EC group or as others have shown it is a consequence of loss of spontaneous control of HIV. Therefore, as no consensus exist further studies comparing variability of immune function between EC and ART can aid in understanding the mechanisms of natural control of HIV. In our recent study (Sperk et al 2021, iScience) we hypothesised that modulated CCR6/CCL20 chemokine axis and CCR2-CCL7-CCL2 signalling can play a protective role in the EC phenotype. Downregulation of CCR2 and CCR6 receptors in lymphocytes and higher plasma abundance of CCL4, CCL7 and CCL20 in EC compared to the HIV-negative controls can provide natural resistance to HIV-infection. In the present study, we further extended our analysis to evaluate the expression profile dynamics of key chemokine receptors, CCR2, CCR3, CCR5 and CCR6, in successfully treated PLWH. We compared well treated PLWH with HIV-1 elite controllers and its association with HIV-1 persistence. Furthermore, cell populations of interest were isolated for liquid chromatography mass spectrometry (LC-MS/MS) based untargeted proteomics analysis to evaluate specific characteristics regulating these cell populations and their role in HIV persistence. Our study provides important understanding of the chemokine receptor dynamics and its role in HIV persistence that differentiate elite controllers from long term treated PLWH.
2022-04-22 | PXD027749 | Pride
Project description:Our previous studies suggest that Th17 cells accumulate within tumor tissues and correlate with recurrence of cervical cancer patients. However, the source of the increased tumor-infiltrating Th17 cells remains poorly understood. We investigated the prevalence, phenotype and trafficking property of Th17 cells in patients with cervical cancer. Our results showed that Th17 cells highly aggregated within tumor tissues in an activated phenotype with markedly increased expression of CCR6. Correspondingly, level of CCL20 in the tumor tissues was significantly higher than that in non-tumor and normal control tissues, and strongly positively associated with Th17 cells. Further, in vitro migration assay showed CCL20 had effective chemotaxis to circulating Th17 cells. In conclusion, Th17 cells are recruited into tumor tissues preferentially through CCR6-CCL20 pathway, which can serve as a novel therapeutic target for cervical cancer.
| S-EPMC4359139 | biostudies-literature
Project description:Neutrophils are critical for the rapid eradication of bacterial pathogens, but they also contribute to the development of multiple organ failure in sepsis. We hypothesized that increasing early recruitment of neutrophils to the focus of infection will increase bacterial clearance and improve survival. Sepsis was induced in mice, using cecal ligation and puncture (CLP); blood samples were collected at 6 and 24 h; and survival was followed for 28 d. In separate experiments, peritoneal bacteria and inflammatory cells were measured. Septic mice predicted to die based on IL-6 levels (Die-P) had higher concentrations of CXCL1 and CXCL2 in the peritoneum and plasma compared with those predicted to live (Live-P). At 6 h, Live-P and Die-P had equivalent numbers of peritoneal neutrophils and bacteria. In Die-P mice the number of peritoneal bacteria increased between 6 and 24 h post-CLP, whereas in Live-P it decreased. The i.p. injection of CXCL1 and CXCL2 in naive mice resulted in local neutrophil recruitment. When given immediately after CLP, CXC chemokines increased peritoneal neutrophil recruitment at 6 h after CLP. This early increase in neutrophils induced by exogenous chemokines resulted in significantly fewer peritoneal bacteria by 24 h [CFU (log) = 6.04 versus 4.99 for vehicle versus chemokine treatment; p < 0.05]. Chemokine treatment significantly improved survival at both 5 d (40 versus 72%) and 28 d (27 versus 52%; p < 0.02 vehicle versus chemokines). These data demonstrate that early, local treatment with CXC chemokines enhances neutrophil recruitment and clearance of bacteria as well as improves survival in the CLP model of sepsis.
| S-EPMC5540308 | biostudies-literature
Project description:Previous pneumococcal experience establishes lung-resident IL-17A-producing CD4+ memory TRM cells that accelerate neutrophil recruitment against heterotypic pneumococci. Herein, we unravel a novel crosstalk between CD4+ TRM cells and lung epithelial cells underlying this protective immunity. Depletion of CD4+ cells in pneumococcus-experienced mice diminished CXCL5 (but not CXCL1 or CXCL2) and downstream neutrophil accumulation in the lungs. Epithelial cells from experienced lungs exhibited elevated mRNA for CXCL5 but not other epithelial products such as GM-CSF or CCL20, suggesting a skewing by CD4+ TRM cells. Genome-wide expression analyses revealed a significant remodeling of the epithelial transcriptome of infected lungs due to infection history, ~80% of which was CD4+ cell-dependent. The CD4+ TRM cell product IL-17A stabilized CXCL5 but not GM-CSF or CCL20 mRNA in cultured lung epithelial cells, implicating posttranscriptional regulation as a mechanism for altered epithelial responses. These results suggest that epithelial cells in experienced lungs are effectively different, owing to their communication with TRM cells. Our study highlights the role of tissue-resident adaptive immune cells in fine-tuning epithelial functions to hasten innate immune responses and optimize defense in experienced lungs, a concept that may apply broadly to mucosal immunology.
| S-EPMC7044037 | biostudies-literature
Project description:Major depressive disorder (MDD) is associated with alterations of GABAergic interneurons, notably somatostatin (Sst) as well as parvalbumin (Pvalb), in cortical brain areas. In addition, the antidepressant effects of rapid-acting drugs are thought to occur via inhibition of GABA interneurons. However, the impact of these interneuron subtypes in affective behaviors as well as in the effects of rapid-acting antidepressants remains to be determined. Here, we used a Cre-dependent DREADD-chemogenetic approach to determine if inhibition of GABA interneurons in the mPFC of male mice is sufficient to produce antidepressant actions, and conversely if activation of these interneurons blocks the rapid and sustained antidepressant effects of scopolamine, a nonselective acetylcholine muscarinic receptor antagonist. Chemogenetic inhibition of all GABA interneurons (Gad1+), as well as Sst+ and Pvalb+ subtypes in the mPFC produced dose and time-dependent antidepressant effects in the forced swim and novelty suppressed feeding tests, and increased synaptic plasticity. In contrast, stimulation of Gad1, Sst, or Pvalb interneurons in mPFC abolished the effects of scopolamine and prevented scopolamine induction of synaptic plasticity. The results demonstrate that transient inhibition of GABA interneurons promotes synaptic plasticity that underlies rapid antidepressant responses.
| S-EPMC8052382 | biostudies-literature