Relevance of Regulatory T Cells during Colorectal Cancer Development

In recent years, there has been a significant increase in the study of own and foreign human factors favoring the development of different types of cancer, including genetic and environmental ones. However, the fact that the immune response plays a fundamental role in the development of immunity and susceptibility to colorectal cancer (CRC) is much stronger. Among the many cell populations of the immune system that participate in restricting or favoring CRC development, regulatory T cells (Treg) play a major role in orchestrating immunomodulation during CRC. In this review, we established concrete evidence supporting the fact that Treg cells have an important role in the promotion of tumor development during CRC, mediating an increasing suppressive capacity which controls the effector immune response, and generating protection for tumors. Furthermore, Treg cells go through a process called “phenotypic plasticity”, where they co-express transcription factors that promote an inflammatory profile. We reunited evidence that describes the interaction between the different effector populations of the immune response and its modulation by Treg cells adapted to the tumor microenvironment, including the mechanisms used by Treg cells to suppress the protective immune response, as well as the different subpopulations of Treg cells participating in tumor progression, generating susceptibility during CRC development. Finally, we discussed whether Treg cells might or might not be a therapeutic target for an effective reduction in the morbidity and mortality caused by CRC.

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Bronchial asthma and helminth invasion: particularity of the cellular immunity

Bulletin of Siberian Medicine ◽

10.20538/1682-0363-2011-3-93-99 ◽

2011 ◽

Vol 10 (3) ◽

pp. 93-99

Author(s):

O. V. Eliseyeva

Keyword(s):

Immune Response ◽

T Cells ◽

Regulatory T Cells ◽

Bronchial Asthma ◽

Cellular Immunity ◽

Allergic Inflammation ◽

Allergic Diseases ◽

Treg Cells ◽

Human Immune Response ◽

Human Immune

In this review we discuss the mechanisms of human immune response modification by helminth in bronchial asthma. Helminth invasion causes increase of level to regulatory T-cells and to suppression of an allergic inflammation in bronchial asthma. Antihelminth therapy leads to decrease of level Treg cells. Deficiency or dysfunction of Treg cells can be a cause of allergic diseases.

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Tumor Infiltrating Regulatory T Cells in Sporadic and Colitis-Associated Colorectal Cancer: The Red Little Riding Hood and the Wolf

International Journal of Molecular Sciences ◽

10.3390/ijms21186744 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6744

Author(s):

Massimo Claudio Fantini ◽

Agnese Favale ◽

Sara Onali ◽

Federica Facciotti

Keyword(s):

Colorectal Cancer ◽

Immune Response ◽

T Cells ◽

Phenotypic Plasticity ◽

Regulatory T Cells ◽

Cancer Progression ◽

Small Cell Lung Carcinoma ◽

Tumor Stage ◽

Cell Lung Carcinoma ◽

Main Driver

Regulatory T cells represent a class of specialized T lymphocytes that suppress unwanted immune responses and size the activation of the immune system whereby limiting collateral damages in tissues involved by inflammation. In cancer, the accumulation of Tregs is generally associated with poor prognosis. Many lines of evidence indicate that Tregs accumulation in the tumor microenvironment (TME) suppresses the immune response against tumor-associated antigens (TAA), thus promoting tumor progression in non-small cell lung carcinoma (NSLC), breast carcinoma and melanoma. In colorectal cancer (CRC) the effect of Tregs accumulation is debated. Some reports describe the association of high number of Tregs in CRC stroma with a better prognosis while others failed to find any association. These discordant results stem from the heterogeneity of the immune environment generated in CRC in which anticancer immune response may coexists with tumor promoting inflammation. Moreover, different subsets of Tregs have been identified that may exert different effects on cancer progression depending on tumor stage and their location within the tumor mass. Finally, Tregs phenotypic plasticity may be induced by cytokines released in the TME by dysplastic and other tumor-infiltrating cells thus affecting their functional role in the tumor. Here, we reviewed the recent literature about the role of Tregs in CRC and in colitis-associated colorectal cancer (CAC), where inflammation is the main driver of tumor initiation and progression. We tried to explain when and how Tregs can be considered to be the “good” or the “bad” in the colon carcinogenesis process on the basis of the available data concluding that the final effect of Tregs on sporadic CRC and CAC depends on their localization within the tumor, the subtype of Tregs involved and their phenotypic plasticity.

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Faculty Opinions recommendation of CD4+CD25+FOXP3+ regulatory T cells suppress anti-tumor immune responses in patients with colorectal cancer.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1059735.512910 ◽

2007 ◽

Author(s):

Filippo La Torre

Keyword(s):

Colorectal Cancer ◽

T Cells ◽

Regulatory T Cells ◽

Immune Responses

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Faculty Opinions recommendation of Activated regulatory T cells are the major T cell type emigrating from the skin during a cutaneous immune response in mice.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.4517974.4832069 ◽

2010 ◽

Author(s):

Deborah Fowell ◽

Michael Overstreet

Keyword(s):

Immune Response ◽

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Cell Type

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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.

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Secretome screening reveals immunomodulating functions of IFNα-7, PAP and GDF-7 on regulatory T-cells

Scientific Reports ◽

10.1038/s41598-021-96184-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Mei Ding ◽

Rajneesh Malhotra ◽

Tomas Ottosson ◽

Magnus Lundqvist ◽

Aman Mebrahtu ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Cell Function ◽

Foxp3 Expression ◽

Treg Cells ◽

Secreted Proteins ◽

External Stimulation ◽

Marker Proteins ◽

Positive Regulators ◽

Conformational Model

AbstractRegulatory T cells (Tregs) are the key cells regulating peripheral autoreactive T lymphocytes. Tregs exert their function by suppressing effector T cells. Tregs have been shown to play essential roles in the control of a variety of physiological and pathological immune responses. However, Tregs are unstable and can lose the expression of FOXP3 and suppressive functions as a consequence of outer stimuli. Available literature suggests that secreted proteins regulate Treg functional states, such as differentiation, proliferation and suppressive function. Identification of secreted proteins that affect Treg cell function are highly interesting for both therapeutic and diagnostic purposes in either hyperactive or immunosuppressed populations. Here, we report a phenotypic screening of a human secretome library in human Treg cells utilising a high throughput flow cytometry technology. Screening a library of 575 secreted proteins allowed us to identify proteins stabilising or destabilising the Treg phenotype as suggested by changes in expression of Treg marker proteins FOXP3 and/or CTLA4. Four proteins including GDF-7, IL-10, PAP and IFNα-7 were identified as positive regulators that increased FOXP3 and/or CTLA4 expression. PAP is a phosphatase. A catalytic-dead version of the protein did not induce an increase in FOXP3 expression. Ten interferon proteins were identified as negative regulators that reduced the expression of both CTLA4 and FOXP3, without affecting cell viability. A transcriptomics analysis supported the differential effect on Tregs of IFNα-7 versus other IFNα proteins, indicating differences in JAK/STAT signaling. A conformational model experiment confirmed a tenfold reduction in IFNAR-mediated ISG transcription for IFNα-7 compared to IFNα-10. This further strengthened the theory of a shift in downstream messaging upon external stimulation. As a summary, we have identified four positive regulators of FOXP3 and/or CTLA4 expression. Further exploration of these Treg modulators and their method of action has the potential to aid the discovery of novel therapies for both autoimmune and infectious diseases as well as for cancer.

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Trichostatin A Promotes the Generation and Suppressive Functions of Regulatory T Cells

Clinical and Developmental Immunology ◽

10.1155/2013/679804 ◽

2013 ◽

Vol 2013 ◽

pp. 1-8 ◽

Cited By ~ 14

Author(s):

Cristian Doñas ◽

Macarena Fritz ◽

Valeria Manríquez ◽

Gabriela Tejón ◽

María Rosa Bono ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Trichostatin A ◽

Gene Promoter ◽

Treg Cells ◽

Specific Subset ◽

Global Increase ◽

And Function ◽

H3 Acetylation

Regulatory T cells are a specific subset of lymphocytes that suppress immune responses and play a crucial role in the maintenance of self-tolerance. They can be generated in the thymus as well as in the periphery through differentiation of naïve CD4+T cells. The forkhead box P3 transcription factor (Foxp3) is a crucial molecule regulating the generation and function of Tregs. Here we show that thefoxp3gene promoter becomes hyperacetylated inin vitrodifferentiated Tregs compared to naïve CD4+T cells. We also show that the histone deacetylase inhibitor TSA stimulated thein vitrodifferentiation of naïve CD4+T cells into Tregs and that this induction was accompanied by a global increase in histone H3 acetylation. Importantly, we also demonstrated that Tregs generated in the presence of TSA have phenotypical and functional differences from the Tregs generated in the absence of TSA. Thus, TSA-generated Tregs showed increased suppressive activities, which could potentially be explained by a mechanism involving the ectonucleotidases CD39 and CD73. Our data show that TSA could potentially be used to enhance the differentiation and suppressive function of CD4+Foxp3+Treg cells.

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