scholarly journals Infectious Tolerance

2002 ◽  
Vol 196 (2) ◽  
pp. 255-260 ◽  
Author(s):  
Helmut Jonuleit ◽  
Edgar Schmitt ◽  
Hacer Kakirman ◽  
Michael Stassen ◽  
Jürgen Knop ◽  
...  
Keyword(s):  
T Cells ◽  
Treg Cell ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Treg Cells ◽  
Cell Contact ◽  
Th Cells ◽  
Self Tolerance ◽  
Infectious Tolerance ◽  
Membrane Bound

Regulatory CD4+CD25+ T cells (Treg) are mandatory for maintaining immunologic self-tolerance. We demonstrate that the cell-cell contact–mediated suppression of conventional CD4+ T cells by human CD25+ Treg cells is fixation resistant, independent from membrane-bound TGF-β but requires activation and protein synthesis of CD25+ Treg cells. Coactivation of CD25+ Treg cells with Treg cell–depleted CD4+ T cells results in anergized CD4+ T cells that in turn inhibit the activation of conventional, freshly isolated CD4+ T helper (Th) cells. This infectious suppressive activity, transferred from CD25+ Treg cells via cell contact, is cell contact–independent and partially mediated by soluble transforming growth factor (TGF)-β. The induction of suppressive properties in conventional CD4+ Th cells represents a mechanism underlying the phenomenon of infectious tolerance. This explains previously published conflicting data on the role of TGF-β in CD25+ Treg cell–induced immunosuppression.

Local and Systemic Induction of an Abundant CD4+CD25+ Regulatory T Cell Population by Non-Hodgkin’s Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 357-357
Author(s):  
S. Mittal ◽  
N.A. Marshall ◽  
L. Duncan ◽  
D.J. Culligan ◽  
R.N. Barker ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Peripheral Blood ◽  
Cd4 T Cells ◽  
Treg Cells ◽  
Cell Contact ◽  
Healthy Controls ◽  
Soluble Factors ◽  
Tissue Samples ◽  
Ann Arbor

Abstract Regulatory T (Treg) cells contribute to immune evasion by malignancies. To investigate their importance in non-Hodgkin’s lymphoma (NHL), we enumerated Treg cells in peripheral blood mononuclear cells (PBMC) and involved tissues from 30 newly diagnosed patients. CD25+FoxP3+CD127lowCD4+ Treg cells were increased markedly in PBMC (median=20.4% CD4 T cells, n=20) versus healthy controls (median=3.2%, n=13; p<0. 001, rank sum test) and correlated with serum lactate dehydrogenase (n=14; Rs=0.79, p <0.0001) and disease stage. The median Treg percentage of CD4 T cells from early stages (Ann Arbor stage I and II, n=4) was 12.2%, whereas it was 25.4% in advanced disease (Ann Arbor stages III, IV or bulky stage II, ≥5cm, n=10; p =0.013). We also enumerated Tr1 cells, both in peripheral blood and involved tissue samples, and again compared with healthy controls but no significant differences were noted. We documented poor proliferation of T cells with mitogen ConA and almost none with recall antigens PPD and DPT in both PBMC and involved tissue samples (n=9). T cell hyporesponsiveness was reversed by depleting CD25+ cells (n=4), or by adding anti-CTLA-4 (n=3), supporting the view that Treg cells explain the systemic immunosuppression seen in NHL. A high proportion of Treg cells was also present in involved tissues (median=38.8% CD4 T cells, n=15) versus reactive nodes (median=11.6%, n=2, p=0.02). Therefore, we tested the hypothesis that a regulatory phenotype is induced from conventional T cells within the tumor microenvironment. When autologous CD25- PBMC fractions were incubated with tumor cells from patients (n=6) in vitro, there was consistent strong induction and then expansion of cells with the CD4+CD25+FoxP3+ phenotype of classic ‘natural’ Treg cells as indicated by CFSE dilution. This induction was dependent on tumor dose and was seen when we depleted lymphoid dendritic cells from the involved tissue cell suspension using anti-CD304, or enriched the tumor cells by positive selection of CD20+ cells. This population was confirmed to be suppressive in function (n=3). We also investigated the mechanisms of this induction. Both cell-cell contact and soluble factors appeared important. In two of four cases, some induction was also noted with transwell experiments or with tumor cell conditioned supernatant, indicating that in these cases soluble factors are also involved apart from direct cell-cell contact mechanism. Reports elsewhere suggest roles for prostaglandin E2, tryptophan catabolism, IL-9 and PD-1 interaction with its ligands in inducing a Treg phenotype. Thus, we used cyclooxygenase inhibitors aspirin and sulindac, the indoleamine 2, 3-dioxygenase (IDO) inhibitor 1-methyl tryptophan (1MT), anti-IL-9 receptor antibody and blocking anti-PDL-1 or anti-PDL-2 antibodies in four samples. None of these reagents inhibited Treg induction apart from one case where both anti-PDL-1 and anti-PDL-2 blocking antibodies inhibited Treg induction. We conclude that NHL cells are powerful inducers of Treg cells, which may represent a new therapeutic target.

Lineage-Plasticity and Inflammatory Change of Human FoxP3+ Regulatory T Cells in Acute Viral Infection: Implication in Immune-Mediated Tissue Injury

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4132-4132
Author(s):  
Yoon Seok Choi ◽  
Jeewon Lee ◽  
Ik-Chan Song ◽  
Deog-Yeon Jo ◽  
Eui-Cheol Shin
Keyword(s):  
T Cells ◽  
Viral Infection ◽  
Treg Cell ◽  
Liver Damage ◽  
Cd4 T Cells ◽  
Treg Cells ◽  
Suppressive Activity ◽  
Suppressive Function ◽  
Acute Viral Infection ◽  
Tnf Α

Abstract FoxP3+ CD4+CD25hi regulatory T (Treg) cells play a major role in maintaining the immune homeostasis by preventing the activation of self-reactive T cells as well as in controlling a series of immune responses in viral infections. Recent studies suggest that lineage-commitment of CD4+T cells, including Treg cells, is not a fixed fate, rather a status with a wide range of plasticity. Functional changes and lineage-plasticity of Treg cells during acute viral infection, especially of human, have not been reported so far. Herein, we investigated whether Treg cells show the functional plasticity and whether such changes can affect the regulation of immunopathology in a human acute viral infection. As a model of human acute viral infection, we used a cohort of patients with acute hepatitis A (AHA), since tissue (liver) injury in AHA is mediated exclusively by activated T cells, not by direct cytopathic effect of virus. To assess the plasticity of Treg cell lineage, first, we examined the production of a variety of inflammatory cytokines from Treg cells following T cell receptor (TCR) stimulation of peripheral blood lymphocytes with anti-CD3/CD28 antibody, using intracellular cytokine staining and multicolor flow cytometry. We found that a significant proportion of FoxP3+ CD4+CD25hi Treg cells produced TNF-α following TCR stimulation in patients with AHA, but not in heathy subjects. Analyses at multiple time points during the course of infection showed that TNF-α production from Treg cells decreased in convalescent phase. Likewise, we observed that liver-infiltrating Treg cells also produced TNF-α after TCR stimulation. Moreover, highly-purified CD4+CD25hiCD127lo/-Treg cells could also produce TNF-α following TCR stimulation, indicating that Treg cells of AHA patients can produce TNF-α in direct response to TCR stimulation. Next, to exclude the possibility that TNF-α might be secreted from transiently FoxP3-expressing activated non-Treg CD4+ T cells, we examined the expression level of CD127 on TNF-α-secreting FoxP3+ CD4+ T cells. TNF-α+ Treg cells expressed CD127 in the level similar to conventional TNF-α- counterpart, and CD127 expression levels of both Treg populations were much lower than FoxP3- CD4+ T cells. Furthermore, DNA methylation analysis of Treg cell-specific demethylated region (TSDR) after sorting TNF-α+ Treg cells revealed completely demethylated pattern in highly conserved CpG island of FOXP3 gene. These findings support that TNF-α is produced from bona fide Treg cells, not from FoxP3-expressing activated non-Treg CD4+T cells. In analysis of immunophenotypes, TNF-α+ Treg cells were enriched in CD45RA-FoxP3lo population, implying their reduced in vivo suppressive activity. Along with the lower level of FoxP3, TNF-α+ Treg cells showed lower level of CD39 expression, a surrogate marker of Treg cell suppressive activity, compared to TNF-α- Treg cells. Furthermore, TNF-α+Treg cells showed a robust evidence of lineage-plasticity toward Th17 lineage, expressing a key transcription factor RORγt. Consistently, they expressed CCR6 and co-produced IL-17A following TCR stimulation, which are the hallmark of Th17 effector function. To analyze the clinical implication of attenuate suppressive function and plasticity shown by TNF-α+ Treg cells, we examined correlation between production of proinflammatory cytokines from Treg cells and severity of liver damage in AHA. As a result, proportion of TNF-α-producing Treg cells closely and linearly correlated with severity of liver damage, suggesting the critical role of TNF-α+ Treg cells in the immunopathogenesis of AHA. However, Treg cell suppression assay in the absence or presence of anti-TNF-α antibody showed that Treg cell suppressive function was not affected by TNF-α blockade. This indicates that attenuated function of TNF-α+Treg cells is not attributed simply to production of a kind of inflammatory cytokine, rather to more complicated reprogramming mechanism. Taken together, these data provide a clear evidence of attenuated suppressive activity and Th17-toward lineage plasticity of FoxP3+ Treg cells, represented by TNF-α production, in a human acute viral infection. Also, we suggest one possible mechanism that lineage plasticity and inflammatory changes of Treg cells could be implicated in the immunopathogenesis of human diseases. Disclosures No relevant conflicts of interest to declare.

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 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 Involvement of Regulatory T Cells in the Immunosuppression Characteristic of Patients with Paracoccidioidomycosis

2010 ◽  
Vol 78 (10) ◽  
pp. 4392-4401 ◽  
Author(s):  
Maria Carolina Ferreira ◽  
Rômulo Tadeu Dias de Oliveira ◽  
Rosiane Maria da Silva ◽  
Maria Heloisa Souza Lima Blotta ◽  
Ronei Luciano Mamoni
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Neutralizing Antibodies ◽  
Transforming Growth Factor ◽  
Paracoccidioides Brasiliensis ◽  
Treg Cells ◽  
Delayed Type Hypersensitivity ◽  
Cell Contact ◽  
Regulatory Activity ◽  
Cell Cell

ABSTRACT Patients with paracoccidioidomycosis (PCM) exhibit a suppression of the cellular immune response characterized by negative delayed-type hypersensitivity (DTH) to Paracoccidioides brasiliensis antigens, the apoptosis of lymphocytes, and high levels of expression of cytotoxic-T-lymphocyte-associated antigen 4 (CTLA-4), interleukin-10 (IL-10), and transforming growth factor β (TGF-β). The aim of this study was to investigate whether and how regulatory T cells (Treg cells) are involved in this immunosuppression by analyzing the number, phenotype, and activity of these cells in patients with active disease (AD group) and patients who had received treatment (TD group). Our results showed that the AD patients had more Treg cells than the TD patients or controls (C group) and also had elevated levels of expression of regulatory markers (glucocorticoid-induced tumor necrosis factor [TNF] receptor-related protein [GITR], CTLA-4, CD95L, LAP-1, and CD38). An analysis of regulatory activity showed that Treg cells from the AD group had greater activity than did cells from the other groups and that cell-cell contact is mandatory for this activity in the C group but was only partially involved in the regulatory activity of cells from AD patients. The addition of anti-IL-10 and anti-TGF-β neutralizing antibodies to the cultures showed that the production of cytokines may be another mechanism used by Treg cells. In conclusion, the elevated numbers of these cells with an increased regulatory phenotype and strong suppressive activity suggest a potential role for them in the immunosuppression characteristic of paracoccidioidomycosis. In addition, our results indicate that while Treg cells act by cell-cell contact, cytokine production also plays an important role.

scholarly journals Study on Quantity and Function of Regulatory T Cell Subsets in Multiple Myeloma and MGUS

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3154-3154
Author(s):  
Jinuo Wang ◽  
Jian Li ◽  
Xinxin Cao ◽  
Hao Cai ◽  
Ai-lin Zhao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Treg Cell ◽  
Cd4 T Cells ◽  
Treg Cells ◽  
Healthy Controls ◽  
Newly Diagnosed ◽  
Inhibition Rate ◽  
Significant Difference ◽  
Normal Controls

Abstract Introduction Almost all multiple myeloma (MM) cases were progressed from a premalignant condition called monoclonal gammopathy of undetermined significance (MGUS). So far, the pathogenesis of myeloma is not yet clear. The immune cells in the tumor microenvironment, such as regulatory T (Treg) cells with a unique immunosuppressive function, play an important role in myelomagenesis. Although there have been reports on Treg cells in MM patients, the results were still in debate. In this study, we performed a comprehensive analysis of peripheral blood (PB) and bone marrow (BM) Treg subsets and aging Treg-like cells in untreated MM patients and individuals with MGUS, which might help further elucidate mechanisms of immune dysfunction during myelomagenesis. Methods Our study included 20 MGUS patients and 26 newly diagnosed MM patients. Flow cytometry was applied to determine the proportion of Treg cell subsets and aging Treg-like cells in PB and BM. Flow sorting technology was used to separate Treg cell subsets and effector T cells in the bone marrow of newly diagnosed MM patients. The inhibitory function was indirectly calculated by detecting proliferation rate of CFSE-labelled effective T cells which were cocultured with different Treg cell subsets. Concentration of IL-10 from the culture supernatants of proliferation assay was measured using ELISA. Results In PB, the proportion of activated Tregs (aTregs, CD4+CD45RA-FoxP3hi) in CD4+ T cells was significantly higher in MGUS and untreated MM patients than healthy controls (P=0.01, P<0.001); there was no difference in the proportion of resting Tregs (rTregs, CD4+CD45RA+FoxP3lo) between MGUS and untreated MM patients compared with healthy adults (P=0.72, P=0.07). There was also no significant difference in the frequencies of non-Tregs (CD4+CD45RA-FoxP3lo) from MGUS and MM patients with normal controls (P=0.22, P=0.67). The proportion of CD4+CD28-FoxP3+ Treg-like cells in CD4+ T cells was gradually increased in MGUS, untreated MM patients than healthy controls (P<0.01, P<0.01); Treg-like cells in newly diagnosed MM patients were significantly higher than those in MGUS patients (P=0.01). In BM, the proportion of aTregs was significantly higher in MGUS, untreated MM patients compared with healthy controls (P<0.01); the proportion of rTregs in MGUS, untreated MM patients was significantly lower than that of controls (P=0.02, P<0.01). However, there was no significant difference in the frequencies of non-Tregs in BM from MGUS and MM patients with normal controls (P=0.14, P=0.88). The proportion of Treg-like cells in CD4+ T cells was significantly higher in MGUS, untreated MM patients compared with healthy controls (P<0.01, P<0.01). Treg-like cells in untreated MM patients were significantly higher than those in MGUS patients (P<0.01). The inhibition rate of aTreg in bone marrow of newly diagnosed MM patients was significantly higher than that of rTreg (P<0.01), while the inhibition rate of non-Treg was significantly lower than that of rTreg cells (P<0.01). The inhibition rates of aTreg (P=0.21), rTreg (P=0.08) and non-Treg (P=0.09) in healthy controls were no difference from those in MM patients. The level of IL-10 secreted by non-Treg in untreated MM patients was notably higher than that of aTreg and rTreg; the ability of cytokine secretion of Treg subsets in MM patients was similar with that of healthy controls. Conclusions There were significant changes in the frequencies of Treg cell subsets and Treg-like cells in peripheral blood and bone marrow of MGUS and MM patients, suggesting that immunomodulatory abnormality has existed in patients at premalignant stage. The immunosuppressive and cytokine secretory functions of Treg subsets in bone marrow of untreated MM patients were intact compared with that in healthy adults. Disclosures No relevant conflicts of interest to declare.

Role for granulocyte colony–stimulating factor in the generation of human T regulatory type 1 cells

Blood ◽  
2002 ◽  
Vol 100 (7) ◽  
pp. 2562-2571 ◽  
Author(s):  
Sergio Rutella ◽  
Luca Pierelli ◽  
Giuseppina Bonanno ◽  
Simona Sica ◽  
Franco Ameglio ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Cell Contact ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Stimulating Factor ◽  
Tgf Β1

Granulocyte colony–stimulating factor (G-CSF) may affect T-cell homeostasis by multiple mechanisms, inducing polarization of cytokine secretion, inhibition of T-cell proliferation, and enhancement of T-cell apoptosis. We analyzed the production of interleukin-10 (IL-10) and transforming growth factor-β1 (TGF-β1) by T cells from healthy volunteer donors treated with recombinant human G-CSF. Highly purified CD4+ T cells obtained before and after G-CSF administration (pre-G and post-G, respectively) were activated using the allogeneic mixed leukocyte reaction. Post-G CD4+T cells produced high levels of IL-10 but undetectable levels of IL-2 and IL-4, whereas the level of TGF-β1 release was comparable to that of pre-G CD4+ T cells. Notably, post-G CD4+ T cells proliferated poorly in response to alloantigens and to recall antigens and suppressed the proliferation of autologous CD4+ T cells in a cell contact–independent and an antigen-nonspecific manner. TGF-β1 and IL-10 were not dispensable for post-G CD4+ T cells to mediate suppression, as shown by neutralization studies. Compared with pre-G CD4+ T cells, alloantigen-activated post-G CD4+ T cells preferentially expressed markers associated with memory T cells, in conjunction with reduced levels of CD28 and CD62L. Collectively, these data demonstrate that CD4+ T cells exposed to G-CSF in vivo acquire the properties of T regulatory (Tr) cells once triggered in vitro through the T-cell receptor, including a peculiar cytokine production profile (IL-10++TGF-β1+IL-2low/−IL-4low/−), an intrinsic low proliferative capacity, and a contact-independent suppression of antigen-driven proliferation. Tr cells generated ex vivo after exposure to G-CSF might be clinically relevant for transplantation medicine and for the treatment of human immune-mediated diseases.

Development of a Modified Skin Explant Assay to Study Treg Suppression of Th17 Cell Mediated GvHD in the Skin

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5434-5434
Author(s):  
Raewyn Broady ◽  
Sarah Q. Crome ◽  
Jessie Yu ◽  
Jan P Dutz ◽  
Megan K Levings
Keyword(s):  
T Cells ◽  
Treg Cell ◽  
Tissue Damage ◽  
Cd4 T Cells ◽  
Th17 Cell ◽  
Th17 Cells ◽  
Acute Gvhd ◽  
Treg Cells ◽  
Haematopoietic Stem Cell ◽  
Graft Versus Host

Abstract Acute graft versus host disease (aGVHD) following haematopoietic stem cell transplantation (HCT) occurs when donor T cells infused with the graft recognise and react to histo-incompatible recipient antigens causing tissue damage. Historically, the inflammatory response in aGVHD was attributed to alloreactive CD4+ T helper and CD8+ cytotoxic T cells and alterations in cytokine production. Recently, a new CD4+ T cell subset, characterised by IL-17 production has been identified. TH17 cells produce high levels of proinflammatory cytokines, including IL-17A, IL-17F, and IL-22, and have been implicated in solid organ rejection and more recently a number of murine studies suggest that Th17 cells play a role in the development of aGVHD. It is well known that FOXP3+ regulatory T cells (Tregs) are critical for the maintenance of self-tolerance, and control the immune response to alloantigens. Murine studies have shown that adoptive transfer of these cells can prevent acute GVHD whereas selective depletion leads to an increased severity. In humans, Tregs also appear to control acute GVHD as they occur at a lower frequency in the peripheral blood patients with aGVHD compared to patients without GVHD. These findings have led to active interest into the use of these cells to prevent or decrease GVHD following allogeneic HCT. It has been reported that in vitro, Th17 cells are resistant to Treg cell mediated suppression of proliferation and IL-17 production, suggesting that the effector functions of Th17 cells might not be susceptible to Treg-cell-mediated inhibition. If true, this would suggest that Treg-based therapies might not be effective at limiting Th17-cell-mediated tissue damage. However, there is currently no evidence regarding whether Treg cells affect the phenotype or function of Th17 cells in tissues. Understanding the interactions between suppressive Tregs and pro-inflammatory T effectors in tissues that are targets of aGVHD, such as the skin, is critical to better define the potential of Tregs as adoptive therapy for the prevention or treatment of aGVHD. In order to address this question, we developed two methods to generate human Th17 cells, one based on over-expression of RORC2 and the other on sorting CCR4+CCR6+CD4+ T cells. We found that ectopic expression of RORC induces a cytokine and chemokine receptor profile analogous to in vivo differentiated Th17 cells. Although expression of RORC2 made CD4+ T cells resistant to Treg-cell mediated suppression of proliferation and IL-17 production, production of IFN-g, TNF-a and IL-6 could be suppressed in these Th17-like cells. In order to further delineate the functional consequence of the interaction between Treg and Th17 cells in tissues we developed a modified the human skin explant model that involves culture of 4 mm punch biopsies of skin with ex vivo Th17 cells (CCR4+CCR6+CD4+ T cells), RORC2 transduced CD4+ T cells, or controls, in the presence or absence of Treg and grading the graft-versus-host reactivity (grades I–IV) histopathologically. Preliminary data suggest that Th17 cells cause significant tissue destruction in this skin explant model, and experiments are ongoing to determine whether Treg cells can counteract these effects.

Role of regulatory T-cells in autoimmunity

2009 ◽  
Vol 116 (8) ◽  
pp. 639-649 ◽  
Author(s):  
Richard J. Mellanby ◽  
David C. Thomas ◽  
Jonathan Lamb
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Treg Cell ◽  
Cell Function ◽  
Cell Subset ◽  
Treg Cells ◽  
Self Tolerance

There has been considerable historical interest in the concept of a specialist T-cell subset which suppresses over-zealous or inappropriate T-cell responses. However, it was not until the discovery that CD4+CD25+ T-cells had suppressive capabilities both in vitro and in vivo that this concept regained credibility and developed into one of the most active research areas in immunology today. The notion that in healthy individuals there is a subset of Treg-cells (regulatory T-cells) involved in ‘policing’ the immune system has led to the intensive exploration of the role of this subset in disease resulting in a number of studies concluding that a quantitative or qualitative decline in Treg-cells is an important part of the breakdown in self-tolerance leading to the development of autoimmune diseases. Although Treg-cells have subsequently been widely postulated to represent a potential immunotherapy option for patients with autoimmune disease, several studies of autoimmune disorders have demonstrated high numbers of Treg-cells in inflamed tissue. The present review highlights the need to consider a range of other factors which may be impairing Treg-cell function when considering the mechanisms involved in the breakdown of self-tolerance rather than focussing on intrinsic Treg-cell factors.

scholarly journals Treg-Resistant Cytotoxic CD4+ T Cells Dictate T Helper Cells in Their Vicinity: TH17 Skewing and Modulation of Proliferation

2021 ◽  
Vol 22 (11) ◽  
pp. 5660
Author(s):  
Cindy Hoeks ◽  
Marjan Vanheusden ◽  
Liesbet M. Peeters ◽  
Piet Stinissen ◽  
Bieke Broux ◽  
...  
Keyword(s):  
T Cells ◽  
Conditioned Medium ◽  
T Helper Cells ◽  
Cd4 T Cells ◽  
Cell Contact ◽  
T Helper ◽  
Th Cells ◽  
Inflammatory Microenvironment ◽  
Helper Cells

Cytotoxic CD4+ T cells (CD4 CTL) are terminally differentiated T helper cells that contribute to autoimmune diseases, such as multiple sclerosis. We developed a novel triple co-culture transwell assay to study mutual interactions between CD4 CTL, conventional TH cells, and regulatory T cells (Tregs) simultaneously. We show that, while CD4 CTL are resistant to suppression by Tregs in vitro, the conditioned medium of CD4 CTL accentuates the suppressive phenotype of Tregs by upregulating IL-10, Granzyme B, CTLA-4, and PD-1. We demonstrate that CD4 CTL conditioned medium skews memory TH cells to a TH17 phenotype, suggesting that the CD4 CTL induce bystander polarization. In our triple co-culture assay, the CD4 CTL secretome promotes the proliferation of TH cells, even in the presence of Tregs. However, when cell−cell contact is established between CD4 CTL and TH cells, the proliferation of TH cells is no longer increased and Treg-mediated suppression is restored. Taken together, our results suggest that when TH cells acquire cytotoxic properties, these Treg-resistant CD4 CTL affect the proliferation and phenotype of conventional TH cells in their vicinity. By creating such a pro-inflammatory microenvironment, CD4 CTL may favor their own persistence and expansion, and that of other potentially pathogenic TH cells, thereby contributing to pathogenic responses in autoimmune disorders.

Sign in / Sign up

Export Citation Format

Share Document