The Th17 Lineage: From Barrier Surfaces Homeostasis to Autoimmunity, Cancer, and HIV-1 Pathogenesis

Wacleche, Vanessa Sue; Landay, Alan; Routy, Jean‐Pierre; Ancuța, Petronela

doi:10.3390/v9100303

Cited by 93 publications

(159 citation statements)

References 290 publications

(549 reference statements)

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“…59,64 Thus, by producing RA, CD16 1 MDDCs may either act as regulatory DCs or activate Th17 cells to promote HIV dissemination at mucosal level. 13,91 Indeed, CD16 1 monocytes express high levels of CX3CR1, 30,31 a chemokine receptor mediating migration into the gut, 92 and they may differentiate into mucosal CD103 1 RALDH2 1 DCs. The pathogenic potential of CD16 1 vs CD16 2 MDDCs in the context of HIV-1 infection may also be mediated by the production of the homeostatic cytokine IL-15, 93,94 pro-inflammatory cytokine TNF-a 41 , and the chemokine CCL22, which may attract CCR4 1 Th17 cells and deliver costimulatory signals essential for HIV replication.…”

Section: Discussionmentioning

confidence: 99%

CD16+ monocytes give rise to CD103+RALDH2+TCF4+ dendritic cells with unique transcriptional and immunological features

et al. 2018

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Classical CD16− vs intermediate/nonclassical CD16+ monocytes differ in their homing potential and biological functions, but whether they differentiate into dendritic cells (DCs) with distinct contributions to immunity against bacterial/viral pathogens remains poorly investigated. Here, we employed a systems biology approach to identify clinically relevant differences between CD16+ and CD16− monocyte-derived DCs (MDDCs). Although both CD16+ and CD16− MDDCs acquire classical immature/mature DC markers in vitro, genome-wide transcriptional profiling revealed unique molecular signatures for CD16+ MDDCs, including adhesion molecules (ITGAE/CD103), transcription factors (TCF7L2/TCF4), and enzymes (ALDH1A2/RALDH2), whereas CD16− MDDCs exhibit a CDH1/E-cadherin+ phenotype. Of note, lipopolysaccharides (LPS) upregulated distinct transcripts in CD16+ (eg, CCL8, SIGLEC1, MIR4439, SCIN, interleukin [IL]-7R, PLTP, tumor necrosis factor [TNF]) and CD16− MDDCs (eg, MMP10, MMP1, TGM2, IL-1A, TNFRSF11A, lysosomal-associated membrane protein 1, MMP8). Also, unique sets of HIV-modulated genes were identified in the 2 subsets. Further gene set enrichment analysis identified canonical pathways that pointed to “inflammation” as the major feature of CD16+ MDDCs at immature stage and on LPS/HIV exposure. Finally, functional validations and meta-analysis comparing the transcriptome of monocyte and MDDC subsets revealed that CD16+ vs CD16− monocytes preserved their superior ability to produce TNF-α and CCL22, as well as other sets of transcripts (eg, TCF4), during differentiation into DC. These results provide evidence that monocyte subsets are transcriptionally imprinted/programmed with specific differentiation fates, with intermediate/nonclassical CD16+ monocytes being precursors for pro-inflammatory CD103+RALDH2+TCF4+ DCs that may play key roles in mucosal immunity homeostasis/pathogenesis. Thus, alterations in the CD16+/CD16− monocyte ratios during pathological conditions may dramatically influence the quality of MDDC-mediated immunity.

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Section: Discussionmentioning

confidence: 99%

CD16+ monocytes give rise to CD103+RALDH2+TCF4+ dendritic cells with unique transcriptional and immunological features

et al. 2018

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“…Th17 cells play an important role in the induction of protective immunity against bacterial and fungal infection at specific mucosal sites such as the gut, lung, and oral cavity (30).…”

Section: Cd8mentioning

confidence: 99%

Tissue-Specific Immunoregulation: A Call for Better Understanding of the “Immunostat” in the Context of Cancer

et al. 2018

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Checkpoint inhibitor therapy has been a breakthrough in cancer research, but only some patients with cancer derive substantial benefit. Although mechanisms underlying sensitivity and resistance to checkpoint inhibitors are being elucidated, the importance of organ-specific regulation of immunity is currently underappreciated. Here, we call for a greater understanding of tissue-specific immunoregulation, namely, “tissue-specific immunostats,” to make advances in treatments for cancer. A better understanding of how individual organs at baseline regulate the immune system could enable an improved precision medicine approach to cancer immunotherapy. Cancer Discov; 8(4); 395–402. ©2018 AACR.

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“…The gastrointestinal tract is a distinctive tissue with physical, biological and immunological barriers, allowing nutrient absorption while preventing the translocation of microbes and their products. HIV infection is associated with modification of the gut microbiota, disruption of the gut epithelial barrier, and increased intestinal permeability [1][2][3][4]. In contrast to the global health improvement occurring in people living with HIV (PLWH) receiving antiretroviral therapy (ART), gut damage persists and translocation of microbial products from the gut lumen into the circulation contributes to inflammatory non-AIDS comorbidities [5].…”

Section: Introductionmentioning

confidence: 99%

Daily variations of gut microbial translocation markers in ART-treated HIV-infected people

et al. 2020

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Background: Increased intestinal barrier permeability and subsequent gut microbial translocation are significant contributors to inflammatory non-AIDS comorbidities in people living with HIV (PLWH). Evidence in animal models have shown that markers of intestinal permeability and microbial translocation vary over the course of the day and are affected by food intake and circadian rhythms. However, daily variations of these markers are not characterized yet in PLWH. Herein, we assessed the variation of these markers over 24 h in PLWH receiving antiretroviral therapy (ART) in a well-controlled environment. Methods: As in Canada, PLWH are predominantly men and the majority of them are now over 50 years old, we selected 11 men over 50 receiving ART with undetectable viremia for more than 3 years in this pilot study. Blood samples were collected every 4 h over 24 h before snacks/meals from 8:00 in the morning to 8:00 the next day. All participants consumed similar meals at set times, and had a comparable amount of sleep, physical exercise and light exposure. Plasma levels of bacterial lipopolysaccharide (LPS) and fungal (1→3)-β-D-Glucan (BDG) translocation markers, along with markers of intestinal damage fatty acid binding protein (I-FABP) and regenerating islet-derived protein-3α (REG3α) were assessed by ELISA or the fungitell assay. Results: Participants had a median age of 57 years old (range 50 to 63). Plasma levels of BDG and REG3α did not vary significantly over the course of the study. In contrast, a significant increase of LPS was detected between 12:00 and 16:00 (Z-score: − 1.15 ± 0.18 vs 0.16 ± 0.15, p = 0.02), and between 12:00 and 24:00 (− 1.15 ± 0.18 vs 0.89 ± 0.26, p < 0.001). The plasma levels of I-FABP at 16:00 (− 0.92 ± 0.09) were also significantly lower, compared to 8:00 the first day (0.48 ± 0.26, p = 0.002), 4:00 (0.73 ± 0.27, p < 0.001) or 8:00 on secondary day (0.88 ± 0.27, p < 0.001). Conclusions: Conversely to the fungal translocation marker BDG and the gut damage marker REG3α, time of blood collection matters for the proper evaluation for LPS and I-FABP as markers for the risk of inflammatory non-AIDS comorbidities. These insights are instrumental for orienting clinical investigations in PLWH.

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The Th17 Lineage: From Barrier Surfaces Homeostasis to Autoimmunity, Cancer, and HIV-1 Pathogenesis

Cited by 93 publications

References 290 publications

CD16+ monocytes give rise to CD103+RALDH2+TCF4+ dendritic cells with unique transcriptional and immunological features

CD16+ monocytes give rise to CD103+RALDH2+TCF4+ dendritic cells with unique transcriptional and immunological features

Tissue-Specific Immunoregulation: A Call for Better Understanding of the “Immunostat” in the Context of Cancer

Daily variations of gut microbial translocation markers in ART-treated HIV-infected people

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