A High-Dimensional Atlas of Human T Cell Diversity Reveals Tissue-Specific Trafficking and Cytokine Signatures

Wong, Michael; Ong, David; Lim, Frances Sheau Huei; Teng, Karen Wei Weng; McGovern, Naomi; Narayanan, Sriram; Ho, Wen Qi; Cerny, Daniela; Tan, Hak Koon; Anicete, Rosslyn; Tan, Bien Keem; Lim, Tony Kiat Hon; Chan, Chung Yip; Cheow, Peng Chung; Lee, Ser Yee; Takano, Angela; Tan, Eng‐Huat; Tam, John Kit Chung; Tan, Ern Yu; Chan, Jerry Kok Yen; Fink, Katja; Bertoletti, Antonio; Ginhoux, Florent; Lafaille, Maria A. Curotto de; Newell, Evan W.

doi:10.1016/j.immuni.2016.07.007

Cited by 227 publications

(281 citation statements)

References 48 publications

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“…Wong et al used mass cytometry to profile CD4+ T cells across eight human tissue types and described 75 different populations, including multiple T h 1 populations for each T H subset. Many cell populations were tissue-specific and differed based the expression of trafficking receptors and cytokine production [47••]. They observed that certain populations co-expressed “key” cytokines like IFN-γ, IL-4, and IL-17A that are typically restricted to a single CD4+ T H subset, in line with previous findings highlighting the phenotypic plasticity between CD4+ T H lineages [48–51], reviewed in [52].…”

Section: High-dimensional Analyses Reveal An Expanded View Of Cd4+ T supporting

confidence: 65%

Leveraging blood and tissue CD4+ T cell heterogeneity at the single cell level to identify mechanisms of disease in rheumatoid arthritis

Fonseka

Rao

Raychaudhuri

2017

Current Opinion in Immunology

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CD4+ T cells have been long known to play an important role in the pathogenesis of rheumatoid arthritis (RA), but the specific cell populations and states that drive the disease have been challenging to identify with low dimensional single cell data and bulk assays. The advent of high dimensional single cell technologies – like single cell RNA-seq or mass cytometry – has offered promise to defining key populations, but brings new methodological and statistical challenges. Recent single cell profiling studies have revealed a broad diversity of cell types among CD4+ T cells, identifying novel populations that are expanded or altered in RA. Here we will review recent findings on CD4+ T cell heterogeneity and RA that have come from single cell profiling studies and discuss the best practices for conducting these studies.

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Section: High-dimensional Analyses Reveal An Expanded View Of Cd4+ T supporting

confidence: 65%

Leveraging blood and tissue CD4+ T cell heterogeneity at the single cell level to identify mechanisms of disease in rheumatoid arthritis

Fonseka

Rao

Raychaudhuri

2017

Current Opinion in Immunology

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“…As expected, CB Tconv control cells exhibited nearly complete methylation of the TSDR (3.8% ± 2.6% demethylated, n = 5; Figure 3B). CD8 + T cell contamination was minimal, particularly in cells expanded from CB (protocol 1: APB Tregs = 0.8% ± 0.4%, CB Tregs = 0.4% ± 0.3%, cryoCB Tregs = 0.5% ± 0.3%; Figure 3C), presumably from the lower frequency of CD8 + T cell in CB 37 . Again, these values were well below the clinical release criteria of ≤5% CD4 − CD8 + contamination.…”

Section: Resultsmentioning

confidence: 99%

Expansion of Human Tregs from Cryopreserved Umbilical Cord Blood for GMP-Compliant Autologous Adoptive Cell Transfer Therapy

Seay

Putnam

Cserny

et al. 2017

Molecular Therapy - Methods & Clinical Development

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Umbilical cord blood is a traditional and convenient source of cells for hematopoietic stem cell transplantation. Thymic regulatory T cells (Tregs) are also present in cord blood, and there is growing interest in the use of autologous Tregs to provide a low-risk, fully human leukocyte antigen (HLA)-matched cell product for treating autoimmune diseases, such as type 1 diabetes. Here, we describe a good manufacturing practice (GMP)-compatible Treg expansion protocol using fluorescence-activated cell sorting, resulting in a mean 2,092-fold expansion of Tregs over a 16-day culture for a median yield of 1.26 × 109 Tregs from single-donor cryopreserved units. The resulting Tregs passed prior clinical trial release criteria for Treg purity and sterility, including additional rigorous assessments of FOXP3 and Helios expression and epigenetic analysis of the FOXP3 Treg-specific demethylated region (TSDR). Compared with expanded adult peripheral blood Tregs, expanded cord blood Tregs remained more naive, as assessed by continued expression of CD45RA, produced reduced IFN-γ following activation, and effectively inhibited responder T cell proliferation. Immunosequencing of the T cell receptor revealed a remarkably diverse receptor repertoire within cord blood Tregs that was maintained following in vitro expansion. These data support the feasibility of generating GMP-compliant Tregs from cord blood for adoptive cell transfer therapies and highlight potential advantages in terms of safety, phenotypic stability, autoantigen specificity, and tissue distribution.

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“…CCR6 regulates cell migration into various anatomic sites including the intestinal mucosa [74-76]. CCR6 expression on CD4 + T-cells is associated with the Th17 lineage commitment [41, 70, 77].…”

Section: Discussionmentioning

confidence: 99%

HIV persists in CCR6+CD4+ T cells from colon and blood during antiretroviral therapy

Gosselin

Salinas

Planas

et al. 2017

Aids

127

181

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Objectives To investigate the contribution of colon and blood CD4+ T-cell subsets expressing the chemokine receptor CCR6 to HIV persistence during ART. Design Matched sigmoid biopsies and blood samples (n=13) as well as leukapheresis (n=20) were collected from chronically HIV-infected individuals receiving ART. Subsets of CD4+ T-cells with distinct differentiation/polarization profiles were identified using surface markers as follows: memory (TM, CD45RA-), central memory (TCM; CD45RA−CCR7+), effector (TEM/TM; CD45RA−CCR7−), Th17 (CCR6+CCR4+), Th1Th17 (CCR6+CXCR3+), Th1 (CCR6−CXCR3+), and Th2 (CCR6−CCR4+). Methods 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. Results Compared to 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 to their CCR6− counterparts (n=13). In blood, integrated HIV-DNA levels were significantly enriched in CCR6+ versus CCR6− TCM of 4/5 individuals and CCR6+ versus CCR6− TEM of 3/5 individuals. Among blood TCM, Th17 and Th1Th17 contributed the most to the pool of cells harboring integrated HIV-DNA despite their reduced frequency compared to 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. Conclusions 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 CCR6+CD4+ T-cells from various anatomic sites.

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A High-Dimensional Atlas of Human T Cell Diversity Reveals Tissue-Specific Trafficking and Cytokine Signatures

Cited by 227 publications

References 48 publications

Leveraging blood and tissue CD4+ T cell heterogeneity at the single cell level to identify mechanisms of disease in rheumatoid arthritis

Leveraging blood and tissue CD4+ T cell heterogeneity at the single cell level to identify mechanisms of disease in rheumatoid arthritis

Expansion of Human Tregs from Cryopreserved Umbilical Cord Blood for GMP-Compliant Autologous Adoptive Cell Transfer Therapy

HIV persists in CCR6+CD4+ T cells from colon and blood during antiretroviral therapy

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