scholarly journals Ionizing radiation modulates the phenotype and function of human CD4+ induced regulatory T cells

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Samantha S. Beauford ◽  
Anita Kumari ◽  
Charlie Garnett-Benson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Ionizing Radiation ◽  
Cancer Cells ◽  
Tumor Immunity ◽  
Foxp3 Expression ◽  
Cytotoxic T Cell ◽  
Suppressive Activity ◽  
Tgf Β1

Abstract Background The use of immunotherapy strategies for the treatment of advanced cancer is rapidly increasing. Most immunotherapies rely on induction of CD8+ tumor-specific cytotoxic T cells that are capable of directly killing cancer cells. Tumors, however, utilize a variety of mechanisms that can suppress anti-tumor immunity. CD4+ regulatory T cells can directly inhibit cytotoxic T cell activity and these cells can be recruited, or induced, by cancer cells allowing escape from immune attack. The use of ionizing radiation as a treatment for cancer has been shown to enhance anti-tumor immunity by several mechanisms including immunogenic tumor cell death and phenotypic modulation of tumor cells. Less is known about the impact of radiation directly on suppressive regulatory T cells. In this study we investigate the direct effect of radiation on human TREG viability, phenotype, and suppressive activity. Results Both natural and TGF-β1-induced CD4+ TREG cells exhibited increased resistance to radiation (10 Gy) as compared to CD4+ conventional T cells. Treatment, however, decreased Foxp3 expression in natural and induced TREG cells and the reduction was more robust in induced TREGS. Radiation also modulated the expression of signature iTREG molecules, inducing increased expression of LAG-3 and decreased expression of CD25 and CTLA-4. Despite the disconcordant modulation of suppressive molecules, irradiated iTREGS exhibited a reduced capacity to suppress the proliferation of CD8+ T cells. Conclusions Our findings demonstrate that while human TREG cells are more resistant to radiation-induced death, treatment causes downregulation of Foxp3 expression, as well as modulation in the expression of TREG signature molecules associated with suppressive activity. Functionally, irradiated TGF-β1-induced TREGS were less effective at inhibiting CD8+ T cell proliferation. These data suggest that doses of radiotherapy in the hypofractionated range could be utilized to effectively target and reduce TREG activity, particularly when used in combination with cancer immunotherapies.

scholarly journals Regulatory T Cells Fail to Suppress Fast Homeostatic Proliferation In Vitro

Life ◽  
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.

scholarly journals 4-1BB regulates NKG2D costimulation in human cord blood CD8+ T cells

Blood ◽  
2008 ◽  
Vol 111 (3) ◽  
pp. 1378-1386 ◽  
Author(s):  
Young-June Kim ◽  
Myung-Kwan Han ◽  
Hal E. Broxmeyer
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cytotoxic Activity ◽  
Cd8 T Cells ◽  
Critical Role ◽  
Cytotoxic T Cell ◽  
Human Cord Blood ◽  
Costimulatory Receptor ◽  
Nkg2d Expression ◽  
Tgf Β1

Abstract Ligation of NKG2D, a potent costimulatory receptor, can be either beneficial or detrimental to CD8+ cytotoxic T cell (CTL) responses. Factors for these diverse NKG2D effects remain elusive. In this study, we demonstrate that 4-1BB, another costimulatory receptor, is an essential regulator of NKG2D in CD8+ T cells. Costimulation of NKG2D caused down-modulation of NKG2D, but induced 4-1BB expression on the cell surface, even in the presence of TGF-β1, which inhibits 4-1BB expression. Resulting NKG2D−4-1BB+ cells were activated but still in an immature state with low cytotoxic activity. However, subsequent 4-1BB costimulation induced cytotoxic activity and restored down-modulated NKG2D. The cytotoxic activity and NKG2D expression induced by 4-1BB on NKG2D+4-1BB+ cells were refractory to TGF-β1 down-modulation. Such 4-1BB effects were enhanced by IL-12. In contrast, in the presence of IL-4, 4-1BB effects were abolished because IL-4 down-modulated NKG2D and 4-1BB expression in cooperation with TGF-β1, generating another CD8+ T-cell type lacking both NKG2D and 4-1BB. These NKG2D−4-1BB− cells were inert and unable to gain cytotoxic activity. Our results suggest that 4-1BB plays a critical role in protecting NKG2D from TGF-β1–mediated down-modulation. Co-expression of NKG2D and 4-1BB may represent an important biomarker for defining competency of tumor infiltrating CD8+ T cells.

Treg phenotype in T-cell lymphomas

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18513-18513
Author(s):  
D. Morales ◽  
B. E. Beltran ◽  
C. Castañeda ◽  
A. Carrasco ◽  
P. Quiñones ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lymphoma ◽  
Foxp3 Expression ◽  
Tumour Cells ◽  
T Cell Lymphoma ◽  
Immunohistochemical Method ◽  
Cytotoxic T Cell ◽  
T Cell Lymphomas ◽  
Treg Phenotype

18513 Background: Foxp3 is a key regulatory gene required for the development and function of: regulatory CD4+CD25high T cells (Treg) specialized in maintaining the balance between immunity and tolerance and activated conventional CD4+CD25low T cells without suppressive activity. Previous studies had reported the origin of Adult T-cell Leukemia/Lymphoma cells (ATLL) in Foxp3 T cells and in other lymphomas types the FOXP3 expression was only detected in the reactive T-cell background. Our objetive was to determine the presence of Treg phenotype cells by the FOXP3 expression in T-cell lymphomas. Methods: A retrospective study was performed on 48 samples collected from diverse T-cell lymphomas in our institution. A highly sensitive immunohistochemical method was used to demonstrate Treg phenotype by FOXP3 protein expression with a mouse monoclonal antibody (clone 236A/E7ABCAM) in most formalin-fixed paraffin-embedded tissue sections from lymph nodes, skin, bone marrow and extranodal sites samples as cavum and stomach. We did not co-stained with CD25 and considered a FOXP3+ tissue when positivity was > 20% of tumor cells. The statistical method was descriptive and survival was calculated using the Kaplan-Meier method. Results: Among the 48 evaluable T-cell lymphomas collected, 33 were ATLL, 8 unspecified peripheral T-cell lymphomas (U-PTCL), 6 mycosis fungoides (MF) and 1 cutaneous aggressive epidermotropic CD8(+) cytotoxic T-cell lymphoma. Among the 33 ATLL: lymphomatous=17, acute=11, smoldering=1, chronic=1, cutaneous=1 and undefined=2. FOXP3 expression in tumour cells was detected in 24% (8/33) of ATLL cases and in 37% (3/8) of U-PTCL. It was negative in MF tumour cells and aggressive epidermotropic CD8(+) cytotoxic T-cell lymphoma Among the ATLL cases FOXP3 positivity were obtained in 35% (6/17) of lymphomatous type; 18% (2/11) of acute ones and none in others ATLL types studied. Interestingly 3 U-PTCL had Treg phenotype and were related to EBV (LMP1 positive); two had extranodal primary ( parotide and cavum) and one was nodal. We failed to demonstrate any correlation between FOXP3 status and survival. Conclusions: Some ATLL and U-PTCL had Treg phenotype. In our work Foxp3 expression was not found to be a prognostic factor. No significant financial relationships to disclose.

Suppressive activity of regulatory T cells correlates with high CD4+ T-cell counts and low T-cell activation during chronic simian immunodeficiency virus infection

AIDS ◽  
2011 ◽  
Vol 25 (5) ◽  
pp. 585-593 ◽  
Author(s):  
Ingrid Karlsson ◽  
Benoît Malleret ◽  
Patricia Brochard ◽  
Benoît Delache ◽  
Julien Calvo ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Infection ◽  
Regulatory T Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cd4 T Cell ◽  
Suppressive Activity ◽  
Cell Counts ◽  
Immunodeficiency Virus

Modulation of cord blood CD8+ T-cell effector differentiation by TGF-β1 and 4-1BB costimulation

Blood ◽  
2005 ◽  
Vol 105 (1) ◽  
pp. 274-281 ◽  
Author(s):  
Young-June Kim ◽  
Teresa M. Stringfield ◽  
Yan Chen ◽  
Hal E. Broxmeyer
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Cord Blood ◽  
Cd8 T Cells ◽  
Cytotoxic T Cell ◽  
Tnf Receptor ◽  
Tnf Receptor Family ◽  
Tgf Β1 ◽  
Receptor Family

Abstract Transforming growth factor-β1 (TGF-β1), an immunosuppressive cytokine, inhibits cytotoxic T cell (CTL) immune responses. In contrast, 4-1BB (CD137), a costimulatory molecule in the tumor necrosis factor (TNF) receptor family, amplifies CTL-mediated antitumor immune responses. We investigated whether TGF-β1 responses could be reversed by 4-1BB costimulation during in vitro differentiation of naive CD8+ T cells into effector CTL cells. TGF-β1 potently suppressed CTL differentiation of human cord blood naive CD8+ T cells as determined by reduced induction of characteristic phenotypes of effector cells and cytotoxic activity. TGF-β1-mediated suppression of CTL differentiation was abrogated by 4-1BB costimulation but not by CD28 or another member in the TNF receptor family, CD30. 4-1BB costimulation suppressed Smad2 phosphorylation induced by TGF-β1, suggesting that 4-1BB effects were at the level of TGF-β1 signaling. 4-1BB effects on the TGF-β1-mediated suppression were enhanced by interleukin 12 (IL-12) but counteracted by IL-4; 4-1BB expression was up- or down-regulated, respectively, by IL-12 and IL-4. IL-4 was more dominant than IL-12 when both cytokines were present during 4-1BB costimulation in the presence of TGF-β1. This indicates critical roles for IL-4 and IL-12 in regulating 4-1BB effects on TGF-β1-mediated suppression. (Blood. 2005;105:274-281)

Prognostic potential of FOXP3 expression in non-small cell lung cancer cells combined with tumor-infiltrating regulatory T cells

Lung Cancer ◽  
2012 ◽  
Vol 75 (1) ◽  
pp. 95-101 ◽  
Author(s):  
Hiroyuki Tao ◽  
Yusuke Mimura ◽  
Keisuke Aoe ◽  
Seiki Kobayashi ◽  
Hiromasa Yamamoto ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Regulatory T Cells ◽  
Small Cell Lung Cancer ◽  
Cancer Cells ◽  
Cell Lung Cancer ◽  
Foxp3 Expression ◽  
Small Cell ◽  
Lung Cancer Cells ◽  
Small Cell Lung

Antigen targeting to endosomal pathway in dendritic cell vaccination activates regulatory T cells and attenuates tumor immunity

Blood ◽  
2006 ◽  
Vol 108 (4) ◽  
pp. 1298-1305 ◽  
Author(s):  
Mikael Maksimow ◽  
Mari Miiluniemi ◽  
Fumiko Marttila-Ichihara ◽  
Sirpa Jalkanen ◽  
Arno Hänninen
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Regulatory T Cells ◽  
Antigen Processing ◽  
Cd4 T Cell ◽  
Cytotoxic T Cell ◽  
Dendritic Cell Vaccination ◽  
Lymphoma Cells ◽  
Self Antigen

Abstract Lymphoma cells are malignant cells of the T- or B-cell lineage that often express many surface markers inappropriately, yet are not recognized as abnormal by the immune system. We modeled this situation by inoculating ovalbumin-expressing E.G7-OVA lymphoma cells into mice that expressed ovalbumin as a self antigen in pancreatic islets, and investigated the efficacy of dendritic cell (DC) vaccination in these mice. Although vaccination with DC-expressing ovalbumin induced strong cytotoxic T-cell immunity, which led to clearance of E.G7-OVA lymphoma cells in naive C57BL/6 mice, DC vaccination was ineffective in mice expressing ovalbumin as a self antigen. Antigen modification to increase its processing via the endosomal processing pathway dramatically increased CD4 T-cell activation but paradoxically, impaired the protective effect of DC vaccination even in naive mice. Depletion of CD25+ T cells (regulatory T cells [Tregs]) prior to vaccination restored the efficacy of DC vaccination and allowed eradication of lymphoma also in mice expressing ovalbumin as a self antigen. We conclude that lymphoma cells may be eradicated using DC vaccination if activation of CD25+ Tregs is simultaneously inhibited, and that intentionally enhanced endosomal antigen processing in DC vaccines may shift the balance from CD4 T-cell help toward stimulation of Tregs.

scholarly journals Targeting ion channel TRPM7 promotes thymic development of Regulatory T cells by increasing IL-2-dependent STAT5 activation

2018 ◽  
Author(s):  
Suresh K. Mendu ◽  
Michael S. Schappe ◽  
Emily K. Moser ◽  
Julia K. Krupa ◽  
Jason S. Rogers ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Ion Channel ◽  
Cell Lineage ◽  
Foxp3 Expression ◽  
List Type ◽  
Thymic Development ◽  
Genetic Deletion

In BriefGenetic deletion of Trpm7 in T-cells or pharmacological inhibition of TRPM7 channel promotes the development of fully functional Treg cells by increasing IL-2Rα and STAT5-dependent FOXP3 expression in the developing thymocytes. The study identifies the ion channel TRPM7 as a putative drug target to increase Treg numbers in vivo and induce immunotolerance.HIGHLIGHTSIon channel TRPM7 controls Treg developmentThe deletion of Trpm7 in the T-cell lineage increases fully functional Treg cells in the peripheryTRPM7 negatively regulates Foxp3 expression by restraining IL-2-dependent STAT5 activationInhibition of TRPM7 channel by FTY720 promotes the development of functional Treg cellsSUMMARYThe thymic development of regulatory T cells (Treg), the crucial suppressors of the effector T cells (Teff), is governed by the transcription factor FOXP3. Despite the clinical significance of Treg cells, there is a dearth of druggable molecular targets capable of increasing Treg numbers in vivo. We report a surprising discovery that TRPM7 restrains Treg development by negatively regulating STAT5-dependent Foxp3 expression. The deletion of Trpm7 potentiates the thymic development of Treg cells, leads to a significantly higher frequency of functional Treg cells in the periphery and renders the mice highly resistant to T cell-dependent hepatitis. The deletion of Trpm7 or the inhibition of TRPM7 channel activity by the FDA-approved prodrug FTY720, increases IL-2 sensitivity through a feed forward positive feedback loop involving high IL-2Rα expression and STAT5 activation. Enhanced IL-2 signaling increases the expression of Foxp3 in thymocytes and promotes the development of Treg cells. Thus, TRPM7 emerges as the first ion channel that can be drugged to increase Treg numbers, revealing a novel pharmacological path toward the induction of immune tolerance.

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