scholarly journals New Insights about Treg and Th17 Cells in HIV Infection and Disease Progression

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Jacqueline María Valverde-Villegas ◽  
Maria Cristina Cotta Matte ◽  
Rúbia Marília de Medeiros ◽  
José Artur Bogo Chies
Keyword(s):  
Hiv Infection ◽  
Disease Progression ◽  
Th17 Cells ◽  
Immune Cell ◽  
Treg Cells ◽  
Proinflammatory Response ◽  
Effector Cells ◽  
T Effector Cells ◽  
Self Tolerance ◽  
And Control

Treg and Th17 cell subsets are characterized by the expression of specific transcriptional factors and chemokine receptor as well as by secretion of specific cytokine and chemokines. These subsets are important to the differentiation, expansion, homing capacity, and recruitment of several different immune cell populations to the site of infection. Whereas Treg cells maintain self-tolerance and control the activation and expansion of autoreactive CD4+T effector cells through an anti-inflammatory response, Th17 cells, in an exacerbated unregulated proinflammatory response, can promote autoimmunity. Despite such apparently opposite functions, Th17 and Treg cells share common characteristics, and their differentiation pathways are interconnected. Recent studies have revealed quite intricate relations between Treg and Th17 cells in HIV infection and progression to AIDS. Considering Treg cells, different subsets were already investigated in the context of HIV infection, indicating a fluctuation in the total number and frequency throughout the disease course. This review focuses on the recent findings regarding the role of regulatory T and Th17 cells in the context of HIV infection, highlighting the importance of the balance between these two subsets on disease progression.

Quantitative and Qualitative Analysis Of Regulatory T Cells (Tregs) Derived From The Peripheral Blood Of Chronic Lymphocytic Leukemia Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5280-5280
Author(s):  
Eleni Dikaia Ioannidou ◽  
Vassiliki Mpakou ◽  
Myrofora Vikentiou ◽  
Eugenia Konsta ◽  
Frieda Kontsioti ◽  
...  
Keyword(s):  
T Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Annexin V ◽  
Treg Cells ◽  
Lymphocytic Leukemia ◽  
Effector Cells ◽  
T Effector Cells ◽  
Healthy Donors

Abstract Introduction T regulatory cells are immunosuppressive cells, which are considered to play an important role in the regulation of immune response to cancer, by restraining autoreactive lymphocytes. Several studies, mostly in solid tumors, revealed that the number of Treg cells increases as the disease progresses and that Treg cells act by suppressing anti-tumor immune response, through the targeting of other immune cells, such as T cells, B cells and dendritic cells. Chronic lymphocytic leukemia (CLL) is a lymphoid malignancy, characterized by both, immunodeficiency and autoimmune disorders. Accumulated data indicate the role of T cells in the pathogenesis and development of CLL and reveal an increased number of Treg cells in CLL patients. The scope of this study is the analysis of the functional role of Tregs derived from the peripheral blood of CLL patients, mainly on B-CLL cells, and its correlation with well known prognostic factors. Methods Treg cells derived from mononuclear cells of 28 untreated B-cell CLL patients with a median age 62 (44-88) and 17 healthy donors were analyzed through Flow cytometry. Patients were classified according to Rai classification as Rai I:19, Rai II:4, Rai III:5 and according to Binet as Binet A: 24, Binet B:3 and Binet C:1. The following antibodies were used for the fluorescence-activated cell sorter (FACS) analysis: 1. CD45Ro-FITC/CD45RA-PE/CD4-ECD/CD25-PC5/CD127-PC7 2. CD1a-FITC/CD137-PE/CD4-ECD/CD25-PC5/CD127-PC7 3. CD95-FITC/cyCD152-PE/CD4-ECD/CD25-PC5/CD127-PC7 4. beads/FoxP3-PE/CD4-ECD/CD25-PC5/CD127-PC7 5. Annexin V-FITC/CD4-ECD/CD25-PC5/CD127-PC7 Moreover, peripheral blood was obtained from 15 patients with B-cell CLL. Mononuclear cells were isolated using Ficoll-Paque gradient centrifugation. CD4+CD25+ (Treg cells), CD4+CD25- (T effectοr cells, Teff), CD5+CD19+ (B-CLL) and CD5+CD19- (Normal B, NB) cells were separated using magnetic antibody cell sorting. To test the functionality of the assayed Tregs, the isolated cell populations were cultured in a 96-well plate (Tregs, Teff, B-CLL, NB cells, Tregs:Teff in a 4:1 ratio, B-cll:Tregs in 1:20 ratio, B-cll:Teff in 1:20 ratio, NB cells:Tregs in 1:20 ratio, NB cells:Teff in 1:20 ratio) and their proliferative capacity was measured using the BrdU assay. Results FACS analysis of the Treg cells resulted at the following observations: (1) The co-expression of the CD45RA-CD45RO markers was significantly higher in patients’ samples than in controls (p=0.047). (2) No significant differences were observed between patients and controls, regarding the expression of the CD1α marker, as well as the expression of CD95 and CD152 markers. (3) The Treg absolute cell number (cells/μL), estimated either as the number of CD4+ CD25+ CD127- cells or as the number of CD4+ CD25+ FoxP3+ cells, was statistically significantly higher in patients’ samples than in controls (CD127- p=0.047, FoxP3+ p= 0.036). (4) Annexin V expression in Treg cells from B- CLL patients was significantly lower compared to controls (p=0.027). Following the purification and culturing of T and B cells from B-cell CLL patients’ samples, functional analysis of the different cell populations was performed using the BrdU proliferation assay. We observed that Tregs were able to significantly suppress the proliferation of the Teff cells (p=0.002). After the co-culturing of NB cells (CD5+CD19-)and Tregs (CD4+CD25+) we found that NB cells seemed to significantly increase the proliferation of Treg cells, compared to the proliferation capacity of the Tregs when cultured alone (p=0.047). Moreover, we observed that Teff (CD4+CD25-) were able to significantly suppress the proliferation of B-CLL cells (CD5+CD19+), when co-cultured (B-CLL: Teff, 1:20 ratio) (p=0.05). Conclusions In B-cell CLL patients, Treg cells are significantly higher and present with lower apoptotic levels compared to healthy donors’ samples. The functional analysis of Treg cells indicates that they can effectively suppress the proliferation of T effector cells. Moreover, T effector cells seem to suppress the proliferation of B-CLL cells, while NB cells increase the proliferation of Treg cells. These observations could probably indicate that at the early stages of the disease, where NB cells are more aberrant, Treg cells’ activity is induced, leading to Teff cells’ suppression and therefore, to an indirect induction of B-CLL cells’ proliferation. Disclosures: No relevant conflicts of interest to declare.

Quantitative and Qualitative Analysis of Regulatory T Cells (Tregs) in B Cell Chronic Lymphocytic Leukemia (B-CLL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2928-2928
Author(s):  
Vassiliki Mpakou ◽  
Dikea-Eleni Ioannidou ◽  
Myrofora Vikentiou ◽  
Eugenia Konsta ◽  
Aris Spathis ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Mononuclear Cells ◽  
Gradient Centrifugation ◽  
Annexin V ◽  
Treg Cells ◽  
Effector Cells ◽  
T Effector Cells ◽  
Healthy Donors ◽  
Brdu Assay

Abstract Introduction: T regulatory cells are immunosuppressive cells considered to play an important role in cancer biology and autoimmunity by suppressing host immune response and autoreactive lymphocytes respectively. Several studies reveal that Treg cells act by suppressing anti-tumor immune response, through the targeting of other immune cells, such as T cells, B cells and dendritic cells. Accumulated data indicate a significant role of T cell dysfunction in the pathogenesis of CLL. Aims: The scope of this study is the analysis of numerical and functional abnormalities of Tregs in B-CLL with the view to elucidate their role in the pathogenesis of the disease. Methods: Treg cells derived from 44 untreated B-CLL patients with a median age 62 and 17 healthy donors were analyzed by Flow cytometry, using the following antibodies: CD45Ro-FITC/CD45RA-PE/CD4-ECD/CD25-PC5/CD127-PC7, CD1a-FITC/CD137-PE/CD4-ECD/CD25-PC5/CD127-PC7, CD95-FITC/cyCD152-PE/CD4-ECD/CD25-PC5/CD127-PC7, beads/FoxP3-PE/CD4-ECD/CD25-PC5/CD127-PC7, Annexin V-FITC/CD4-ECD/CD25-PC5/CD127-PC7. For the functional analysis, peripheral blood was obtained from 20 patients with B-CLL. Mononuclear cells were isolated using Ficoll-Paque gradient centrifugation. CD4+ CD25+ (Treg cells), CD4+ CD25- (T effectοr cells, Teff), CD5+ CD19+ (B-CLL) and CD5- CD19+ (Normal B, NB) cells were separated using magnetic antibody cell sorting. To test the functionality of the assayed Tregs, the isolated cell populations were cultured in a 96-well plate (Tregs, Teff, B-CLL cells, NB cells, B-CLL cells: Tregs in 1:20 ratio, B-CLL cells: Teff in 1:20 ratio, NB cells: Tregs in 1:20 ratio, NB cells: Teff in 1:20 ratio) and their proliferative capacity was measured using the BrdU assay. To further analyze the functional role of Tregs, peripheral blood was obtained from 22 patients with CLL and 22 healthy donors. Mononuclear cells were isolated using Ficoll-Paque gradient centrifugation. CD4+ CD25+ CD127dim/- (Treg cells), CD5+ CD19+ (B-CLL) and CD5- CD19+ (Normal B, NB) cells were separated using magnetic antibody cell sorting and were co-cultured in a 96-well plate in a 1:10 ratio. The apoptosis of B cells was determined by the Annexin V/PI method. Results: FACS analysis of the Treg cells resulted at the following observations: The Treg absolute cell number (cells/μL), estimated either as the number of CD4+ CD25+ CD127- cells or as the number of CD4+ CD25+ FoxP3+ cells, was statistically significantly higher in patients' samples than in controls (CD127- 21.65 vs 7.35, p=0.001; FoxP3+ 20.42 vs 6.5, p= 0.001). Annexin V expression in Treg cells from BCLL patients was significantly lower compared to controls (3.626 vs 38.615, p=0.003). The functional analysis of Treg cells through BrdU assay indicated that CLL Tregs were able to suppress the proliferation of Teff cells (p=0.002) and that Teff cells were in turn able to significantly suppress the proliferation of B-CLL cells (p=0.05). Moreover, FACS analysis through Annexin V/PI method indicated that Treg CLL cells significantly decrease the apoptosis rate of NB cells after their co-culturing, compared to NB cells (p<0,02). On the contrary, healthy donors derived Treg cells significantly increase the apoptosis of B-CLL cells after their co-culturing, compared to B-CLL cells (p<0.025). Interestingly, no significant alterations were observed after culturing NB cells with Tregs from healthy donors and B-CLL cells with Treg CLL cells. Conclusions: In CLL patients, Treg cells are significantly higher and present with lower apoptotic levels compared to healthy donors. The functional analysis indicates that T effector cells suppress the proliferation of B-CLL cells and T effector cells are suppressed by Tregs indicating that the increased number of Tregs observed in CLL contributes indirectly to the proliferation of the CLL clone. These data are further supported by our observations that CLL derived Treg cells appear rather incapable of inducing apoptosis of both NB cells and B-CLL cells, in contrast to normal Tregs, suggesting an immunoediting effect of B-CLL cells on Tregs which negatively affects the functionality of the latter. Therefore, Treg cells in CLL do not efficiently eliminate the abnormal clone and play an important role in the pathogenesis of the disease. The molecular underlying mechanisms need to be further elucidated. Disclosures No relevant conflicts of interest to declare.

scholarly journals Transcriptomic profiling of plaque psoriasis and cutaneous T cell subsets during treatment with secukinumab

2019 ◽  
Author(s):  
Jared Liu ◽  
Hsin-Wen Chang ◽  
Kristen M. Beck ◽  
Sahil Sekhon ◽  
Timothy H. Schmidt ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Plaque Psoriasis ◽  
Immune Cell ◽  
T Cell Subsets ◽  
Skin Tissue ◽  
Rapid Reduction ◽  
Effector Cells ◽  
Lesional Skin ◽  
T Effector Cells

AbstractThe IL17A inhibitor secukinumab is efficacious for the treatment of psoriasis. In order to define its mechanism of action, it is important to understand its impact on psoriatic whole skin tissue as well as specific skin-resident immune cell populations such as T lymphocytes. In this study, we treated 15 moderate-to-severe plaque psoriasis patients with secukinumab and characterized the longitudinal transcriptomic changes of whole lesional skin tissue and cutaneous CD4+ T effector cells (Teffs), CD4+ T regulatory cells (Tregs), and CD8+ T effector cells during 12 weeks of treatment. Secukinumab was clinically effective, with 100%, 47%, and 27% of patients in the study achieving PASI75, PASI90, and PASI100 by week 12, respectively. At baseline prior to treatment, we observed that IL17A overexpression predominates in psoriatic CD8+ T cells rather than Teffs, supporting the importance of IL-17-secreting CD8+ T cells (Tc17) compared to IL-17-secreting CD4+ T cells (Th17) cells in the pathogenesis of psoriasis. Although secukinumab targets only IL17A, we observed rapid reduction of IL17A, IL17F, IL23A, IL23R, and IFNG expression in lesional skin as soon as 2 weeks after initiation of treatment and normalization of expression by week 12. Secukinumab treatment resulted in resolution of 89-97% of psoriasis-associated expression differences in both bulk tissue and T cell subsets by week 12 of treatment. Overall, secukinumab appears to rapidly reverse many of the molecular hallmarks of psoriasis.

scholarly journals Anergy into T regulatory cells: an integration of metabolic cues and epigenetic changes at the Foxp3 conserved non-coding sequence 2

F1000Research ◽  
2018 ◽  
Vol 7 ◽  
pp. 1938 ◽  
Author(s):  
Milagros Silva Morales ◽  
Daniel Mueller
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
T Regulatory Cells ◽  
Immune Cell ◽  
Tolerance Induction ◽  
Short Review ◽  
Treg Cells ◽  
Peripheral Tolerance ◽  
Protective Mechanisms ◽  
Self Tolerance

Peripheral immune self-tolerance relies on protective mechanisms to control autoreactive T cells that escape deletion in the thymus. Suppression of autoreactive lymphocytes is necessary to avoid autoimmunity and immune cell–mediated damage of healthy tissues. An intriguing relationship has emerged between two mechanisms of peripheral tolerance—induction of anergy and Foxp3+ regulatory T (Treg) cells—and is not yet well understood. A subpopulation of autoreactive anergic CD4 T cells is a precursor of Treg cells. We now hypothesize that phenotypic and mechanistic features of Treg cells can provide insights to understand the mechanisms behind anergy-derived Treg cell differentiation. In this short review, we will highlight several inherent similarities between the anergic state in conventional CD4 T cells as compared with fully differentiated natural Foxp3+ Treg cells and then propose a model whereby modulations in metabolic programming lead to changes in DNA methylation at the Foxp3 locus to allow Foxp3 expression following the reversal of anergy.

scholarly journals Treg/Th17 Cell Balance in Patients with Hepatitis B Virus-Related Acute-on-Chronic Liver Failure at Different Disease Stages

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Nian-Hua Tan ◽  
Bin Chen ◽  
Jie Peng ◽  
Shan Du
Keyword(s):  
Hepatitis B Virus ◽  
Hepatitis B ◽  
Liver Failure ◽  
Disease Progression ◽  
Peripheral Blood ◽  
Th17 Cells ◽  
Treg Cells ◽  
Chronic Liver Failure ◽  
B Virus ◽  
Disease Stages

Background. T-helper 17 (Th17) and CD4+CD25+ T-regulatory (Treg) cells play important roles in the pathogenesis of hepatitis B virus-related acute-on-chronic liver failure (HBV-ACLF). This study is aimed at investigating shifts in Treg/Th17 balance in the peripheral blood of HBV-ACLF patients at different disease stages. Methods. Sixty HBV-ACLF patients, admitted to the First Hospital of Hunan University of Chinese Medicine, China, including early-stage ( n = 20 ), middle-stage ( n = 20 ), and late-stage patients ( n = 20 ), were enrolled in the study. In addition, 20 patients with chronic hepatitis B and 20 healthy volunteers were also included in the study as controls. Flow cytometry, cytometric bead array, and quantitative real-time PCR protocols were used to evaluate the expression of Treg and Th17 cells as well as of related cytokines. Results. The levels of Th17 cells and their effectors interleukin- (IL-) 17A, IL-23, and tumor necrosis factor-α increased with disease progression. Similarly, Treg cells and their effector cytokines transforming growth factor-β and IL-10 also increased. Although Treg and Th17 levels were positively correlated, the latter were always at higher numbers. Noteworthy, the Treg/Th17 ratio gradually decreased and was negatively correlated with ACLF severity. FoxP3 levels in the peripheral blood gradually decreased with ACLF progression, whereas ROR-γt gradually increased. Serum c-reactive protein, procalcitonin, and lipopolysaccharide were also upregulated with disease progression and positively correlated with Th17 abundance. Further, Th17, IL-17A, and IL-23 were independent risk factors for ACLF. A prognostic model for HBV-ACLF was established, with a correct prediction rate of 90.00% (54/60). Conclusion. Treg/Th17 imbalance occurs throughout the pathogenic course of HBV-ACLF, with an imbalance shift toward Th17. Hence, the Th17-mediated inflammatory response drives HBV-ACLF-associated inflammation and supports the pathological mechanisms of liver failure.

scholarly journals Treg Enhancing Therapies to Treat Autoimmune Diseases

2020 ◽  
Vol 21 (19) ◽  
pp. 7015
Author(s):  
Peter J. Eggenhuizen ◽  
Boaz H. Ng ◽  
Joshua D. Ooi
Keyword(s):  
T Cells ◽  
Autoimmune Disease ◽  
Autoimmune Diseases ◽  
Treg Cell ◽  
Cell Subset ◽  
Treg Cells ◽  
Immune Homeostasis ◽  
T Effector Cells ◽  
High Affinity ◽  
Self Tolerance

Regulatory T cells (Tregs) are a small yet critical subset of CD4+ T cells, which have the role of maintaining immune homeostasis by, for example, regulating self-tolerance, tumor immunity, anti-microbial resistance, allergy and transplantation rejection. The suppressive mechanisms by which Tregs function are varied and pleiotropic. The ability of Tregs to maintain self-tolerance means they are critical for the control and prevention of autoimmune diseases. Irregularities in Treg function and number can result in loss of tolerance and autoimmune disease. Restoring immune homeostasis and tolerance through the promotion, activation or delivery of Tregs has emerged as a focus for therapies aimed at curing or controlling autoimmune diseases. Such therapies have focused on the Treg cell subset by using drugs to suppress T effector cells and promote Tregs. Other approaches have trialed inducing tolerance by administering the autoantigen via direct administration, by transient expression using a DNA vector, or by antigen-specific nanoparticles. More recently, cell-based therapies have been developed as an approach to directly or indirectly enhance Treg cell specificity, function and number. This can be achieved indirectly by transfer of tolerogenic dendritic cells, which have the potential to expand antigen-specific Treg cells. Treg cells can be directly administered to treat autoimmune disease by way of polyclonal Tregs or Tregs transduced with a receptor with high affinity for the target autoantigen, such as a high affinity T cell receptor (TCR) or a chimeric antigen receptor (CAR). This review will discuss the strategies being developed to redirect autoimmune responses to a state of immune tolerance, with the aim of the prevention or amelioration of autoimmune disease.

scholarly journals Vitamin A Impairs the Reprogramming of Tregs into IL-17-Producing Cells during Intestinal Inflammation

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Gabriela Tejón ◽  
Valeria Manríquez ◽  
Jaime De Calisto ◽  
Felipe Flores-Santibáñez ◽  
Yessia Hidalgo ◽  
...  
Keyword(s):  
T Cells ◽  
Vitamin A ◽  
Intestinal Inflammation ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Transfer Model ◽  
Effector Cells ◽  
T Effector Cells

Maintaining the identity of Foxp3+regulatory T cells (Tregs) is critical for controlling immune responses in the gut, where an imbalance between Tregs and T effector cells has been linked to inflammatory bowel disease. Accumulating evidence suggests that Tregs can convert into Th17 cells and acquire an inflammatory phenotype. In this study, we used an adoptive transfer model of Ag-specific T cells to study the contribution of different factors to the reprogramming ofin vitro-generated Treg cells (iTreg) into IL-17-producing cells in a mouse model of gut inflammationin vivo. Our results show that intestinal inflammation induces the reprogramming of iTreg cells into IL-17-producing cells and that vitamin A restrains reprogramming in the gut. We also demonstrate that the presence of IL-2 during thein vitrogeneration of iTreg cells confers resistance to Th17 conversion but that IL-2 and retinoic acid (RA) cooperate to maintain Foxp3 expression following stimulation under Th17-polarizing conditions. Additionally, although IL-2 and RA differentially regulate the expression of different Treg cell suppressive markers, Treg cells generated under different polarizing conditions present similar suppressive capacity.

scholarly journals Post-Transplant Cyclophosphomide Spares Granzyme B Expression in T Regulatory Cells (Treg), but Not in CD8+ T and NK Cells after Allogeneic HSCT

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5422-5422
Author(s):  
Mikhail Drokov ◽  
Elena N. Parovichnikova ◽  
Larisa A. Kuzmina ◽  
Vera Vasilieva ◽  
Ekaterina Mikhaltsova ◽  
...  
Keyword(s):  
Nk Cells ◽  
Granzyme B ◽  
Treg Cells ◽  
High Dose ◽  
Cd4 Cells ◽  
Becton Dickinson ◽  
Effector Cells ◽  
Allogeneic Hsct ◽  
T Effector Cells ◽  
Post Transplant

Abstract Introduction Allogenic bone marrow transplantation (allo-HSCT) with high-dose, post-transplantation cyclophosphamide (CY) nowadays has become an alternative for standard immunosuppression. Many groups have shown that high dose CY after allo-HSCT selectively deplete alloreactive T effector cells and downregulate Granzyme B expression in CD8+ T and NK cells after allogeneic HSCT. Despite that fact there is no data about other T cell populations, such as Tregs and their immunosuppression abilities after post-transplant CY. We studied Granzyme B expression in Treg on day +14 after allo-HSCT with post-transplant CY and standard immunosuppression. Patients and methods. Peripheral blood samples were collected in EDTA-tubes at day +14 after allo-HSCT in patients with hematological malignancies with post-BMT-CY alone (n=8) and patients with standard immunosuppression (post-HSCT CSA, MMF or MTX at standard dose) (n=18). The anti-CD4-PE-Cy7, anti-CD25-APC, anti-CD127-FITC and anti-Granzyme B-PE (Becton Dickinson, USA) antibodies were used to determine Treg cells population as CD4+ CD25high CD127low. We did not include anti-FoxP3 antibodies as FoxP3 is not so specific in humans and particularly after allo-HSCT due to technical difficulties, several isoforms and etc. CD4- lymphocytes (certainly containing CD8+ and NK-cells population that obligatorily express granzyme B) were used as internal positive control to define population of CD4+ CD25high CD127low GranzymeB+ cells and gMFI (geometric mean fluorescence intensity). 50000 of CD4+ cells were analyzed on a BD FACSCanto II (Becton Dickinson, USA). Results. Mann-Whitney U test was used to test for differences between Granzyme B+ Treg cells after post-transplant-CY alone and in a group of standard immunosuppression. The percent of CD4+ CD25high CD127low GranzymeB+ cells among CD4+ cells at day +14 after post-transplant CY alone was statistically higher (30.1±21,9; p=0.018*) than in patients with standard immunosuppression (3,52±1,56) (see Chart 1). There is no differences in Granzyme B expression (gMFI) in CD4+ CD25high CD127low cells after post-transplant-CY (2131,8±412,7) alone and in a group of standard immunosuppression (1718,17±316,8; p=0.541). It's worth to note that probably this mechanism in combination with depletion of alloreactive T effector cells and downregulation of Granzyme B expression in CD8+ T and NK cells help to prevent aGVHD in this group of patients. Conclusion We suggest that post-transplant CY spares Granzyme B expression in Tregs in a patients with post-transplant-CY and help to prevent aGVHD development in this group of patients. Despite the fact that the analyzed group is small, obtained data is important and needs further investigation. Figure 1. Granzyme B expression in Tregs after post-transplant-CY alone and in a group of standard immunosuppression. Figure 1. Granzyme B expression in Tregs after post-transplant-CY alone and in a group of standard immunosuppression. Disclosures No relevant conflicts of interest to declare.

scholarly journals Human Amniotic Mesenchymal Stem Cells Inhibit aGVHD in Humanized NPG Mice by Regulating Balance of Treg Versus T Effector Cells

2021 ◽  
Author(s):  
Ya Gao ◽  
Weiru Li ◽  
Xiaoyin Bu ◽  
Ying Xu ◽  
Shengchun Cai ◽  
...  
Keyword(s):  
T Cells ◽  
Mouse Models ◽  
Treg Cells ◽  
Control Group ◽  
Lymphocyte Infiltration ◽  
Humanized Mouse ◽  
Effector Cells ◽  
T Effector Cells ◽  
Target Organs ◽  
Human T Cells

Abstract Background: Acute graft versus host disease(aGVHD) occurs when immunocompetent T cells in the donated tissue recognize the recipient as foreign after allo-HSCT, which can severely affect quality of life. Although previous studies indicated that MSC may be a salvage therapeutic agent for aGVHD, the mechanism is not yet fully clear. The aim of this study was to explore the therapeutic efficacy and underlying mechanisms of hAMSCs transplantation for humanized aGVHD mouse model.Methods: We established a novel xenogeneic (xeno)-aGVHD humanized mouse models by transplanting purified human T cells from peripheral blood into immunodeficient NOD-PrkdcscidIl2rγnull (NPG) mouse. In those mouse models, lymphocyte infiltration of target organs was detected by HE staining method and immunohistochemistry respectively. The biological characteristics of hAMSCs were investigated. hAMSCs labeled with GFP were administered to NPG mice to explore the homing ability of hAMSCs. Mice are divided into normal(control) group, aGVHD group and hAMSCs treatment group. After 3 days of injection of PBMC, hAMSCs and PBS were given into the different groups. T effector and Treg cells levels of each group in target organs were detected by flow cytometry and cytometric bead array (CBA).Results: We successfully established xenogeneic aGVHD “humanized model” by using NOD-PrkdcscidIl2rγnull (NPG) mice, which showed lymphocytes infiltration in the liver, spleen and lung. hAMSCs therapy improved systemic inflammation and inhibited aGVHD in humanized mouse through reduced villous blunting and lymphocyte infiltration into the lamina propria of the gut while reducing vascular endothelialitis and lymphocyte infiltration into the parenchyma of the liver and lung. In addition, hAMSCs suppresses xenogenesis CD3+/CD4+ and CD3+/CD8+ T cell concentration and increases the proportion of Treg cells. Our data also show that hAMSC can reduce the level of IL-17A, INF-γ, TNF and IL-2 that involved in the pathogenesis of aGVHD target organs.Conclusions: NPG murine environment is capable of activating human T cells to produce aGVHD pathology to mimic aGVHD in humans. hAMSCs controlled aGVHD by decreasing inflammatory cytokine secretion within target organs through modulating balance of Treg versus T effector cells in humanized mice.

Regulation of Autoreactive CD4 T Cells by FoxO1 Signaling in CNS Autoimmunity

2021 ◽  
Author(s):  
Emma E. Kraus ◽  
Laura Kakuk-Atkins ◽  
Marissa F. Farinas ◽  
Mathew Jeffers ◽  
Amy E. Lovett-Racke ◽  
...  
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Foxp3 Expression ◽  
Treg Cells ◽  
Th1 Cells ◽  
T Effector Cells ◽  
Cns Autoimmunity

Abstract BackgroundMyelin-specific CD4 T effector cells (Teffs), Th1 and Th17 cells, are encephalitogenic in experimental autoimmune encephalomyelitis (EAE), a well-defined murine model of multiple sclerosis (MS) and implicated in MS pathogenesis. Forkhead box O 1 (FoxO1) is a conserved effector molecule in PI3K/Akt signaling and critical in the differentiation of CD4 T cells into T helper subsets. However, it is still unclear whether FoxO1 may be a target for redirecting CD4 T cell differentiation and benefit CNS autoimmunity. MethodsUsing a selective FoxO1 inhibitor AS1842856, we determined the effects of FoxO1 inhibition in regulating myelin-specific Th1 and Th17 cells, and the transcriptional balance of T-bet and Foxp3 in myelin-specific CD4 T cells from EAE mice. The effects of AS1842856 in regulating the encephalitogenicity of myelin-specific T cells and the expansion of human Th1 cells from MS patients were also characterized. Furthermore, we characterized the potential role of FoxO1 in mediating PD-1 signaling in CD4 T cells, critical for regulating Teff and Treg cells. ResultsInhibition of FoxO1 suppressed the differentiation and expansion of Th1 cells. Moreover, the transdifferentiation of Th17 cells into encephalitogenic Th1-like cells was suppressed by FoxO1 inhibition upon reactivation of myelin-specific CD4 T cells from mice with EAE. When FoxO1 was inhibited in myelin-specific CD4 T cells, the transcriptional balance skewed from the Th1 transcription factor T-bet toward the Treg transcription factor Foxp3. Myelin-specific CD4 T cells treated with the FoxO1 inhibitor were less encephalitogenic in adoptive transfer EAE studies compared to control-treated cells. Inhibition of FoxO1 in T cells from MS patients significantly suppressed the expansion of Th1 cells. Furthermore, the immune checkpoint programmed cell death protein-1 (PD-1)-induced Foxp3 expression in CD4 T cells was impaired by FoxO1 inhibition, consistent with a bias toward Treg induction. ConclusionsThese data illustrate an important role of FoxO1 signaling in CNS autoimmunity via regulating autoreactive Teff and Treg balance.

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