Human Regulatory T Cells From Umbilical Cord Blood Display Increased Repertoire Diversity and Lineage Stability Relative to Adult Peripheral Blood

Motwani, Keshav; Peters, Leeana D.; Vliegen, Willem H; Elsayed, Ahmed G; Seay, Howard R.; Lopez, Maria-Cecilia; Baker, Henry V.; Posgai, Amanda L.; Brusko, Todd M.; Perry, Daniel J.; Bacher, Rhonda; Larkin, Joseph; Haller, Michael J.

doi:10.3389/fimmu.2020.00611

Cited by 34 publications

(27 citation statements)

References 150 publications

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“…And found that both CD25+ cells at day 0 and iTregs at day 21 expressed all the 24 TCRs ( 30 ). In addition, Motwani et al demonstrated that effector Tregs could clonally expand in the late decidua during normal pregnancy, but could not expand in peripheral blood of humans ( 62 ). Therefore, the expanded iTreg cells were mainly transformed from CD4+CD25+ T cells rather than pTreg proliferation.…”

Section: Discussionmentioning

confidence: 99%

Single-Cell Sequencing Reveals the Transcriptome and TCR Characteristics of pTregs and in vitro Expanded iTregs

et al. 2021

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Regulatory T cells (Tregs) play a critical role in the maintenance of immune tolerance and tumor evasion. However, the relative low proportion of these cells in peripheral blood and tissues has hindered many studies. We sought to establish a rapamycin-based in vitro Treg expansion procedure in patients diagnosed with colorectal cancer and perform single-cell sequencing to explore the characteristics of Treg cells. CD25+ cells enriched from peripheral blood mononuclear cells (PBMC) of colorectal tumor patients were cultured in X-VIVO15 medium, supplemented with 5% human AB serum, L-glutamine, rapamycin, interleukin-2 (IL-2), and Dynabeads human Treg expander for 21 days to expand Tregs. Treg cells with satisfactory phenotype and function were successfully expanded from CD4+CD25+ cells in patients with colorectal cancer. The median expansion fold was 75 (range, 20–105-fold), and >90.0% of the harvest cells were CD4+CD25+CD127dim/− cells. The ratio of CD4+CD25+Foxp3+ cells exceeded 60%. Functional assays showed that iTregs significantly inhibited CD8+T cell proliferation in vitro. Single-cell sequencing showed that the transcriptome of pTreg (CD4+CD25+CD127dim/− cells isolated from PBMC of colorectal cancer patients) and iTreg (CD4+CD25+CD127dim/− cells expanded in vitro according to the above regimen) cells were interlaced. pTregs exhibited enhanced suppressive function, whereas iTregs exhibited increased proliferative capacity. TCR repertoire analysis indicated minimal overlap between pTregs and iTregs. Pseudo-time trajectory analysis of Tregs revealed that pTregs were a continuum composed of three main branches: activated/effector, resting and proliferative Tregs. In contrast, in vitro expanded iTregs were a mixture of proliferating and activated/effector cells. The expression of trafficking receptors was also different in pTregs and iTregs. Various chemokine receptors were upregulated in pTregs. Activated effector pTregs overexpressed the chemokine receptor CCR10, which was not expressed in iTregs. The chemokine CCL28 was overexpressed in colorectal cancer and associated with poor prognosis. CCR10 interacted with CCL28 to mediate the recruitment of Treg into tumors and accelerated tumor progression. Depletion of CCR10+Treg cells from tumor microenvironment (TME) could be used as an effective treatment strategy for colorectal cancer patients. Our data distinguished the transcriptomic characteristics of different subsets of Treg cells and revealed the context-dependent functions of different populations of Treg cells, which was crucial to the development of alternative therapeutic strategies for Treg cells in autoimmune disease and cancer.

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Section: Discussionmentioning

confidence: 99%

Single-Cell Sequencing Reveals the Transcriptome and TCR Characteristics of pTregs and in vitro Expanded iTregs

et al. 2021

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“…The shorter TCRs in neonatal T cells do not limit TCR diversity. The results from deep sequencing and single cell sequencing demonstrate higher diversity of TCR repertoire in human neonatal Tconv and Tregs when compared to adult ones ( 28 , 29 ). In addition, UCB Treg cells are also shown to have more clones with TCRs specific for autoantigens ( 28 ).…”

Section: T Cell Repertoire Before Thymic Selection In Early Lifementioning

confidence: 97%

“…Indeed, specific and competent CD8 + T cell responses against a range of viral infections (Vesicular Stomatitis Virus, Vaccinia Virus, and Lymphocytic Choriomeningitis Virus) in vivo have been observed in murine Tdt -deficient or neonatal T cells ( 34 , 43 , 44 ). In human samples, T cells in UCB had higher level of CD5 expression and higher precursor frequency for certain tumor-associated antigens or pathogens than T cells in adults ( Table 1 ) ( 28 , 42 , 45 ). Together with delayed TdT expression and similar TCR sequencing feature between human fetal T cells and mouse neonatal T cells, it is believed, although more evidence is needed, that human TCR repertoire also has high cross-reactivity.…”

Section: T Cell Repertoire Before Thymic Selection In Early Lifementioning

confidence: 99%

T cell Tolerance in Early Life

et al. 2020

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T cell-mediated immune tolerance is a state of unresponsiveness of T cells towards specific self or non-self antigens. This is particularly essential during prenatal/neonatal period when T cells are exposed to dramatically changing environment and required to avoid rejection of maternal antigens, limit autoimmune responses, tolerate inert environmental and food antigens and antigens from non-harmful commensal microorganisms, promote maturation of mucosal barrier function, yet mount an appropriate response to pathogenic microorganisms. The cell-intrinsic and cell extrinsic mechanisms promote the generation of prenatal/neonatal T cells with distinct features to meet the complex and dynamic need of tolerance during this period. Reduced exposure or impaired tolerance in early life may have significant impact on allergic or autoimmune diseases in adult life. The uniqueness of conventional and regulatory T cells in human umbilical cord blood (UCB) may also provide certain advantages in UCB transplantation for hematological disorders.

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“…Alternative sources and methods for expansion of Tregs that maintain their intrapopulational heterogeneity and retention of CD62L-positive, less differentiated Tregs should be investigated. Interestingly, umbilical cord Tregs exhibit increased repertoire diversity and are better at maintaining Treg lineage stability (73). It is possible that the naive source of Tregs from umbilical cords and improved expansion methods could lead to longer-lasting Tregs that retain their suppressive capacity.…”

Section: Exogenous Treg Therapymentioning

confidence: 99%

Function, Failure, and the Future Potential of Tregs in Type 1 Diabetes

Bettini

2021

Diabetes

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Critical insights into the etiology of type 1 diabetes (T1D) came from genome-wide association studies that unequivocally connected genetic susceptibility to immune cell function. At the top of the susceptibility are genes involved in regulatory T-cell (Treg) function and development. The advances in epigenetic and transcriptional analyses have provided increasing evidence for Treg dysfunction in T1D. These are well supported by functional studies in mouse models and analysis of peripheral blood during T1D. For these reasons, Tregbased therapies are at the forefront of research and development and have a tangible probability to deliver a long-sought-after successful immune-targeted treatment for T1D. The current challenge in the field is whether we can directly assess Treg function at the tissue site or make informative interpretations based on peripheral data. Future studies focused on Treg function in pancreatic lymph nodes and pancreas could provide key insight into the ultimate mechanisms underlying Treg failure in T1D. In this Perspective we will provide an overview of current literature regarding Treg development and function in T1D and how this knowledge has been applied to Treg therapies.

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Human Regulatory T Cells From Umbilical Cord Blood Display Increased Repertoire Diversity and Lineage Stability Relative to Adult Peripheral Blood

Cited by 34 publications

References 150 publications

Single-Cell Sequencing Reveals the Transcriptome and TCR Characteristics of pTregs and in vitro Expanded iTregs

Single-Cell Sequencing Reveals the Transcriptome and TCR Characteristics of pTregs and in vitro Expanded iTregs

T cell Tolerance in Early Life

Function, Failure, and the Future Potential of Tregs in Type 1 Diabetes

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