Persistence of naive CD45RA+ regulatory T cells in adult life

AbstractRegulatory T cells (TREGs) constitutively expressing CD4, CD25, and the transcription factor Foxp3 can prevent a wide range of experimental and spontaneous autoimmune diseases in mice. In humans, CD4+CD25bright T cells, predominantly within the CD45RO+ activated/memory subset in adults and the CD45RA+ naive T-cell subset in infants, are considered to be the equivalent subset. Using novel combinations of monoclonal antibodies (mAbs), we examined expression of CD25 in human infant thymus, cord blood, adult peripheral blood, lymph node, and spleen. In addition to the CD4+CD25bright T cells, subfractionation on the basis of CD45 splice variants indicated that all samples contained a second distinct population of cells expressing a slightly lower level of CD25. In adult peripheral blood, this population expressed a naive CD45RA+ phenotype. The corresponding population in lymph node, spleen, and cord blood showed some evidence of activation, and expressed markers characteristic of TREGs, such as cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). Sorted CD4+CD25+CD45RA+ T cells from both cord and adult blood expressed very high levels of mRNA for Foxp3 and manifested equivalent suppressive activity in vitro, indicating that they are bone fide members of the regulatory T-cell lineage. Targeting naive TREGs in adults may offer new means of preventing and treating autoimmune disease.

Download Full-text

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

Frontiers in Immunology ◽

10.3389/fimmu.2020.00611 ◽

2020 ◽

Vol 11 ◽

Cited By ~ 1

Author(s):

Keshav Motwani ◽

Leeana D. Peters ◽

Willem H. Vliegen ◽

Ahmed Gomaa El-sayed ◽

Howard R. Seay ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Cord Blood ◽

Umbilical Cord ◽

Umbilical Cord Blood ◽

Peripheral Blood ◽

Repertoire Diversity ◽

Lineage Stability ◽

Adult Peripheral Blood

Download Full-text

Transcriptome profiling of human thymic CD4+ and CD8+ T cells compared to primary peripheral T cells

10.21203/rs.2.18314/v2 ◽

2020 ◽

Author(s):

Hanna Helgeland ◽

Ingvild Gabrielsen ◽

Helle Akselsen ◽

Arvind Y.M. Sundaram ◽

Siri Tennebø Flåm ◽

...

Keyword(s):

Cell Cycle ◽

T Cells ◽

T Cell ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Cell Subset ◽

Functional Enrichment ◽

Valuable Insight ◽

Thymic Tissue ◽

Adult Peripheral Blood

Abstract Background: The thymus is a highly specialized organ of the immune system where T cell precursors develop and differentiate into self-tolerant CD4+ or CD8+ T cells. No studies to date have investigated how the human transcriptome profiles differ, between T cells still residing in the thymus and T cells in the periphery. Results: We have performed high-throughput RNA sequencing to characterize the transcriptomes of primary single positive (SP) CD4+ and CD8+ T cells from infant thymic tissue, as well as primary CD4+ and CD8+ T cells from infant and adult peripheral blood, to enable the comparisons across tissues and ages. In addition, we have assessed the expression of candidate genes related to autoimmune diseases in thymic CD4+ and CD8+ T cells. The thymic T cells showed the largest number of uniquely expressed genes, suggesting a more diverse transcription in thymic T cells. Comparing T cells of thymic and blood origin, revealed more differentially expressed genes, than between infant and adult blood. Functional enrichment analysis revealed an over-representation of genes involved in cell cycle and replication in thymic T cells, whereas infant blood T cells were dominated by immune related terms. Comparing adult and infant blood T cells, the former was enriched for inflammatory response, cytokine production and biological adhesion, while upregulated genes in infant blood T cells were associated with cell cycle, cell death and gene expression. Conclusion: This study provides valuable insight into the transcriptomes of the human primary SP T cells still residing within the thymus, and offers a unique comparison to primary blood derived T cells. Interestingly, the majority of autoimmune disease associated genes were expressed in one or more T cell subset, however ~11% of these were not expressed in frequently studied adult peripheral blood.

Download Full-text

Comparative study of regulatory T cells expanded ex vivo from cord blood and adult peripheral blood

Immunology ◽

10.1111/j.1365-2567.2012.03573.x ◽

2012 ◽

Vol 136 (2) ◽

pp. 218-230 ◽

Cited By ~ 18

Author(s):

Huahua Fan ◽

Jie Yang ◽

Jun Hao ◽

Yana Ren ◽

Liang Chen ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Comparative Study ◽

Cord Blood ◽

Peripheral Blood ◽

Ex Vivo ◽

Adult Peripheral Blood

Download Full-text

PD-1 Expression by Lymph Node and Intratumoral Regulatory T Cells Is Associated with Lymph Node Metastasis in Pancreatic Cancer

Cancers ◽

10.3390/cancers12102756 ◽

2020 ◽

Vol 12 (10) ◽

pp. 2756

Author(s):

Adrian M. Seifert ◽

Annabel Eymer ◽

Max Heiduk ◽

Rebekka Wehner ◽

Antje Tunger ◽

...

Keyword(s):

T Cells ◽

Lymph Node ◽

T Cell ◽

Lymph Node Metastasis ◽

Regulatory T Cells ◽

Lymph Nodes ◽

Cell Subset ◽

Pancreatic Head ◽

Node Metastasis ◽

Draining Lymph Nodes

Pancreatic ductal adenocarcinoma (PDAC) is characterized by a mostly immunosuppressive microenvironment. Tumor-draining lymph nodes (TDLN) are a major site for priming of tumor-reactive T cells and also tumor metastasis. However, the phenotype and function of T cells in TDLNs from PDAC patients is unknown. In this study, lymph nodes from the pancreatic head (PH), the hepatoduodenal ligament (HDL) and the interaortocaval (IAC) region were obtained from 25 patients with adenocarcinoma of the pancreatic head. Additionally, tumors and matched blood were analyzed from 16 PDAC patients. Using multicolor flow cytometry, we performed a comprehensive analysis of T cells. CD4+ T cells were the predominant T cell subset in PDAC-draining lymph nodes. Overall, lymph node CD4+ and CD8+ T cells had a similar degree of activation, as measured by CD69, inducible T cell co-stimulator (ICOS) and CD137 (4-1BB) expression and interferon-γ (IFNγ) secretion. Expression of the inhibitory receptor programmed death 1 (PD-1) by lymph node and tumor-infiltrating regulatory T cells (Tregs) correlated with lymph node metastasis. Collectively, Treg cells and PD-1 are two relevant components of the immunosuppressive network in PDAC-draining lymph nodes and may be particularly attractive targets for combinatorial immunotherapeutic strategies in selected patients with node-positive PDAC.

Download Full-text

Expansion of regulatory T cells from umbilical cord blood and adult peripheral blood CD4+CD25+ T cells

Immunologic Research ◽

10.1007/s12026-014-8488-1 ◽

2014 ◽

Vol 60 (1) ◽

pp. 105-111 ◽

Cited By ~ 7

Author(s):

Syh-Jae Lin ◽

Chun-Hao Lu ◽

Dah-Chin Yan ◽

Pei-Tzu Lee ◽

Hsiu-Shan Hsiao ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Cord Blood ◽

Umbilical Cord ◽

Umbilical Cord Blood ◽

Peripheral Blood ◽

Adult Peripheral Blood

Download Full-text

Comparative Study of Regulatory T Cell Function of HumanCD25+CD4+T Cells from Thymocytes, Cord Blood, and Adult Peripheral Blood

Clinical and Developmental Immunology ◽

10.1155/2008/305859 ◽

2008 ◽

Vol 2008 ◽

pp. 1-12 ◽

Cited By ~ 36

Author(s):

Wakae Fujimaki ◽

Nozomu Takahashi ◽

Kei Ohnuma ◽

Masayoshi Nagatsu ◽

Hiromi Kurosawa ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Cord Blood ◽

T Cell Activation ◽

Peripheral Blood ◽

Expression Level ◽

Regulatory Function ◽

Suppressive Activity ◽

Functional Differences ◽

Adult Peripheral Blood

CD25+CD4+regulatory T cells suppress T cell activation and regulate multiple immune reactions in in vitro and in vivo studies. To define the regulatory function of humanCD25+CD4+T cells at various stages of maturity, we investigated in detail the functional differences ofCD25+CD4+T cells from thymocytes, cord blood (CB), and adult peripheral blood (APB). CBCD25+CD4+T cells displayed low-FOXP3 protein expression level and had no suppressive activity. In contrast,CD25+CD4+T cells from thymocytes or APB expressed high expression level of FOXP3 protein associated with significant suppressive activity. Although CBCD25+CD4+T cells exhibited no suppressive activity, striking suppressive activity was observed following expansion in culture associated with increased FOXP3 expression and a shift from theCD45RA+to theCD45RA−phenotype. These functional differences inCD25+CD4+T cells from Thy, CB, and APB hence suggest a pathway of maturation for Treg in the peripheral immune system.

Download Full-text

CD4 T Cell Subset Profiling in Biliary Atresia Reveals ICOS- Regulatory T Cells as a Favourable Prognostic Factor

SSRN Electronic Journal ◽

10.2139/ssrn.3294752 ◽

2018 ◽

Author(s):

Shuhao Zhang ◽

Shyamal Goswami ◽

Jiaqiang Ma ◽

Lu Meng ◽

Youping Wang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Prognostic Factor ◽

Regulatory T Cells ◽

Biliary Atresia ◽

Cell Subset ◽

Cd4 T Cell ◽

T Cell Subset

Download Full-text

Regulatory T Cells Fail to Suppress Fast Homeostatic Proliferation In Vitro

Life ◽

10.3390/life11030245 ◽

2021 ◽

Vol 11 (3) ◽

pp. 245

Author(s):

Daniil Shevyrev ◽

Valeriy Tereshchenko ◽

Elena Blinova ◽

Nadezda Knauer ◽

Ekaterina Pashkina ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Autoimmune Diseases ◽

Peripheral Blood ◽

Treg Cells ◽

Homeostatic Proliferation ◽

Suppressive Activity ◽

Healthy Donors

Homeostatic proliferation (HP) is a physiological process that reconstitutes the T cell pool after lymphopenia involving Interleukin-7 and 15 (IL-7 and IL-15), which are the key cytokines regulating the process. However, there is no evidence that these cytokines influence the function of regulatory T cells (Tregs). Since lymphopenia often accompanies autoimmune diseases, we decided to study the functional activity of Tregs stimulated by HP cytokines from patients with rheumatoid arthritis as compared with that of those from healthy donors. Since T cell receptor (TCR) signal strength determines the intensity of HP, we imitated slow HP using IL-7 or IL-15 and fast HP using a combination of IL-7 or IL-15 with anti-CD3 antibodies, cultivating Treg cells with peripheral blood mononuclear cells (PBMCs) at a 1:1 ratio. We used peripheral blood from 14 patients with rheumatoid arthritis and 18 healthy volunteers. We also used anti-CD3 and anti-CD3 + IL-2 stimulation as controls. The suppressive activity of Treg cells was evaluated in each case by the inhibition of the proliferation of CD4+ and CD8+ cells. The phenotype and proliferation of purified CD3+CD4+CD25+CD127lo cells were assessed by flow cytometry. The suppressive activity of the total pool of Tregs did not differ between the rheumatoid arthritis and healthy donors; however, it significantly decreased in conditions close to fast HP when the influence of HP cytokines was accompanied by anti-CD3 stimulation. The Treg proliferation caused by HP cytokines was lower in the rheumatoid arthritis (RA) patients than in the healthy individuals. The revealed decrease in Treg suppressive activity could impact the TCR landscape during lymphopenia and lead to the proliferation of potentially self-reactive T cell clones that are able to receive relatively strong TCR signals. This may be another explanation as to why lymphopenia is associated with the development of autoimmune diseases. The revealed decrease in Treg proliferation under IL-7 and IL-15 exposure can lead to a delay in Treg pool reconstitution in patients with rheumatoid arthritis in the case of lymphopenia.

Download Full-text

Cord blood T lymphocytes lack constitutive perforin expression in contrast to adult peripheral blood T lymphocytes

Blood ◽

10.1182/blood.v85.6.1540.bloodjournal8561540 ◽

1995 ◽

Vol 85 (6) ◽

pp. 1540-1546 ◽

Cited By ~ 64

Author(s):

C Berthou ◽

S Legros-Maida ◽

A Soulie ◽

A Wargnier ◽

J Guillet ◽

...

Keyword(s):

T Lymphocytes ◽

Cord Blood ◽

Nk Cells ◽

Peripheral Blood ◽

Cell Subset ◽

Cytolytic Activity ◽

Lower Percentage ◽

Target Cells ◽

Perforin Expression ◽

Adult Peripheral Blood

Perforin is the cytolytic pore-forming protein, which alone can be responsible for the lethal hit in one of the killing mechanisms used by natural killer (NK) cells or cytotoxic T lymphocytes. In this study, perforin expression was investigated in cord blood (CB) lymphocytes to determine their killing potential in vivo. The majority of CB CD3- NK cells had the protein. Compared with adult perforin-positive NK cells, a significantly lower percentage of cells expressing CD56 and CD57, the related neural cell adhesion molecules, was found (P = .0001). Perforin was also present in a unique immature CB NK-cell subset, characterized by cytoplasmic CD3 antigen (Ag) expression. In CB, very few CD8 perforin-positive T lymphocytes could be detected, but they were in significant numbers in adult peripheral blood (P = .02). A substantial proportion of these cells (70% +/- 23%) lacked the CD28 T-cell coactivation Ag, and they were able to exert NK-like, major histocompatibility complex nonrestricted cytolytic activity. CD4+ and gamma delta-T cells expressing perforin were absent from CB, but low numbers of such cells were detected in adult peripheral blood (P = .0001). Therefore, the spontaneous cytolytic activity of CB lymphocytes appeared to be dependent on well-represented perforin-positive NK cells, which were shown to efficiently lyse NK-sensitive target cells.

Download Full-text