The influence of humoral factors of homeostatistic proliferation on t-regulatory cells in vitro

Shevyrev, Daniil; Блинова, Е. А.; Козлов, В. А.

doi:10.20538/1682-0363-2019-1-286-293

Cited by 9 publications

(11 citation statements)

References 33 publications

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“…At the same time, the amount of Treg-cells was lower without stimulation than in the samples from peripheral blood before cultivation (6.2±1.5%). This result agrees with our previous data [8]. To directly evaluate the influence of homeostatic cytokines -IL-7 and IL-15 on the expression of FoxP3, we assessed the FoxP3 MFI in Treg-cells at different stimulation conditions (Figure 1).…”

Section: Resultssupporting

confidence: 90%

Influence of Homeostatic Cytokines – Il-7 and Il-15 on T-Regulatory Cells in Vitro

Shevyrev

Козлов

2021

Med. immunol.

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Cytokines IL-7 and IL-15 are the most important humoral factors providing T-conventional cell pool reconstitution during homeostatic proliferation caused by lymphopenia. However, whether these cytokines can provide homeostatic maintenance and proliferation of T-regulatory (Treg) cells is largely unknown. Considering the association between homeostatic proliferation and the development of autoimmunity, we decided to investigate the ability of these factors to cause differentiation of Treg-cells into Th17-lymphocytes. Therefore, the purpose of this study was to investigate the influence of humoral factors of homeostatic proliferation (IL-7 and IL-15) on Treg-cells in vitro. The study used peripheral blood sampled from 22 healthy donors. PBMC fraction was isolated by Ficoll density gradient centrifugation. Proliferation was induced by IL-7, IL-15, and by a combination of IL-2 with anti-CD3-antibodies. The proliferation intensity of Tregs was evaluated by flow cytometry using CFSE in PBMC cultures by phenotype CD3+CD4+CD25+FoxP3+ and in the previously purified population of CD3+CD4+CD25+CD127lo-cells. In this case Treg-cells were obtained by immunomagnetic separation from PBMCs using a MACS Treg Isolation Kit. Also, the RORyt expression in CD3+CD4+CD25+FoxP3+-cells was evaluated during cultivation. Here, we have shown that IL-7 and IL-15 could support Treg-cells by number and phenotype. Also, we revealed that these factors provide FoxP3 expression in Treg-cells; meanwhile, stimulation with IL-2 + anti-CD3 can also cause induction of FoxP3 expression de novo in conventional CD4+ cells. Also, we have shown that IL-7 and IL-15 can cause lower-intensity proliferation of Treg-cells in comparison with IL-2 + anti-CD3. Herewith homeostatic cytokines didn’t have the ability to induce RORyt expression in both T-regulatory cells and CD4+ conventional T-lymphocytes. Thus, it has been shown that IL-7 and IL-15 can potentially participate in maintaining the total pool of Treg-cells during lymphopenia, when IL-2 deficiency occurs, without causing the induction of RORyt expression. However, how homeostatic cytokines affect the functional activity of Treg-cells remains unclear and requires further investigation.

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Section: Resultssupporting

confidence: 90%

Influence of Homeostatic Cytokines – Il-7 and Il-15 on T-Regulatory Cells in Vitro

Shevyrev

Козлов

2021

Med. immunol.

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“…To further investigate this issue, the HLA-DR activation marker expression on Treg lymphocytes was determined. The expression of this molecule was previously found to be associated with elevated FoxP3 expression ( 14 ). HLA-DR + Treg lymphocytes are activated inflammation-associated Treg cells predominant in inflammation foci in RA, and they can recirculate and emerge in peripheral blood.…”

Section: Resultsmentioning

confidence: 89%

“…For the following experiments, 12 donors and 12 patients with RA (DAS-28 >3.2) were randomly selected from the general group, who were comparable by sex and age, and the expression of CD86, CTLA-4, PD-L1, HLA-DR and CCR4 (the gating strategy is shown in Fig. 5 ), which are involved in the functional activity of Treg cells ( 14 ), was investigated. A total of 6 patients had new-onset RA and six were receiving DMARD therapy.…”

Section: Resultsmentioning

confidence: 99%

“…The Treg ability to produce regulatory cytokines, TGF-β and IL-10, was also studied. In addition, the researchers studied the Treg migration potential via CCR4 expression ( 12 ) and the extent of their activation by HLA-DR expression ( 13 , 14 ). Given that T-cell receptors (TCRs) are involved in the trans-endocytosis of CD80/86 molecules with CTLA-4 involvement ( 15 ), to the best of our knowledge, the present study was the first to propose using CD86 molecules as a marker of the Treg/antigen presenting cell (APC) interaction intensity, which may be representative of the contact suppressor activity of Treg cells against a specific range of antigens.…”

Section: Introductionmentioning

confidence: 99%

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T‑regulatory cells from patients with rheumatoid arthritis retain suppressor functions in vitro

et al. 2021

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“…In addition, CCR4 + Treg cells are characterized by an activated phenotype and high suppressive activity [ 51 , 52 ]. HLA-DR is one of the key cell surface molecules expressed on antigen-presenting cells, but is also expressed on activated Treg cells with high FoxP3 expression [ 29 , 53 ]. Such Tregs with HLA-DR expression exhibit early contact suppression activity [ 54 ].…”

Section: Discussionmentioning

confidence: 99%

Regulatory T Cells Fail to Suppress Fast Homeostatic Proliferation In Vitro

Shevyrev

Tereshchenko

Блинова

et al. 2021

Life

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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.

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The influence of humoral factors of homeostatistic proliferation on t-regulatory cells in vitro

Cited by 9 publications

References 33 publications

Influence of Homeostatic Cytokines – Il-7 and Il-15 on T-Regulatory Cells in Vitro

Influence of Homeostatic Cytokines – Il-7 and Il-15 on T-Regulatory Cells in Vitro

T‑regulatory cells from patients with rheumatoid arthritis retain suppressor functions in vitro

Regulatory T Cells Fail to Suppress Fast Homeostatic Proliferation In Vitro

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