Loss of Functional Suppression by CD4+CD25+ Regulatory T Cells in Patients with Multiple Sclerosis

CD4+CD25+ regulatory T cells contribute to the maintenance of peripheral tolerance by active suppression because their deletion causes spontaneous autoimmune diseases in mice. Human CD4+ regulatory T cells expressing high levels of CD25 are suppressive in vitro and mimic the activity of murine CD4+CD25+ regulatory T cells. Multiple sclerosis (MS) is an inflammatory disease thought to be mediated by T cells recognizing myelin protein peptides. We hypothesized that altered functions of CD4+CD25hi regulatory T cells play a role in the breakdown of immunologic self-tolerance in patients with MS. Here, we report a significant decrease in the effector function of CD4+CD25hi regulatory T cells from peripheral blood of patients with MS as compared with healthy donors. Differences were also apparent in single cell cloning experiments in which the cloning frequency of CD4+CD25hi T cells was significantly reduced in patients as compared with normal controls. These data are the first to demonstrate alterations of CD4+CD25hi regulatory T cell function in patients with MS.

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Role of regulatory T-cells in autoimmunity

Clinical Science ◽

10.1042/cs20080200 ◽

2009 ◽

Vol 116 (8) ◽

pp. 639-649 ◽

Cited By ~ 20

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.

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Signaling through C5a receptor and C3a receptor diminishes function of murine natural regulatory T cells

Journal of Experimental Medicine ◽

10.1084/jem.20121525 ◽

2013 ◽

Vol 210 (2) ◽

pp. 257-268 ◽

Cited By ~ 132

Author(s):

Wing-hong Kwan ◽

William van der Touw ◽

Estela Paz-Artal ◽

Ming O. Li ◽

Peter S. Heeger

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Cell Function ◽

Foxp3 Expression ◽

C5a Receptor ◽

Self Tolerance ◽

T Cell Immune Responses

Thymus-derived (natural) CD4+ FoxP3+ regulatory T cells (nT reg cells) are required for immune homeostasis and self-tolerance, but must be stringently controlled to permit expansion of protective immunity. Previous findings linking signals transmitted through T cell–expressed C5a receptor (C5aR) and C3a receptor (C3aR) to activation, differentiation, and expansion of conventional CD4+CD25− T cells (T conv cells), raised the possibility that C3aR/C5aR signaling on nT reg cells could physiologically modulate nT reg cell function and thereby further impact the induced strength of T cell immune responses. In this study, we demonstrate that nT reg cells express C3aR and C5aR, and that signaling through these receptors inhibits nT reg cell function. Genetic and pharmacological blockade of C3aR/C5aR signal transduction in nT reg cells augments in vitro and in vivo suppression, abrogates autoimmune colitis, and prolongs allogeneic skin graft survival. Mechanisms involve C3a/C5a-induced phosphorylation of AKT and, as a consequence, phosphorylation of the transcription factor Foxo1, which results in lowered nT reg cell Foxp3 expression. The documentation that C3a/C3aR and C5a/C5aR modulate nT reg cell function via controlling Foxp3 expression suggests targeting this pathway could be exploited to manipulate pathogenic or protective T cell responses.

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Rapamycin enriches for CD4+ CD25+ CD27+ Foxp3+ regulatory T cells in ex vivo-expanded CD25-enriched products from healthy donors and patients with multiple sclerosis

Cytotherapy ◽

10.1080/14653240601145223 ◽

2007 ◽

Vol 9 (2) ◽

pp. 144-157 ◽

Cited By ~ 30

Author(s):

Ca Keever-Taylor ◽

Mb Browning ◽

Bd Johnson ◽

Rl Truitt ◽

Cn Bredeson ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Regulatory T Cells ◽

Ex Vivo ◽

Healthy Donors

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Characterizing T Cells in SCID Patients Presenting with Reactive or Residual T Lymphocytes

Clinical and Developmental Immunology ◽

10.1155/2012/261470 ◽

2012 ◽

Vol 2012 ◽

pp. 1-9 ◽

Cited By ~ 9

Author(s):

Atar Lev ◽

Amos J. Simon ◽

Luba Trakhtenbrot ◽

Itamar Goldstein ◽

Meital Nagar ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Cell Function ◽

Severe Combined Immunodeficiency ◽

Cell Activity ◽

Mhc Ii ◽

Cell Functions ◽

Circulating T Cells

Introduction. Patients with severe combined immunodeficiency (SCID) may present with residual circulating T cells. While all cells are functionally deficient, resulting in high susceptibility to infections, only some of these cells are causing autoimmune symptoms.Methods. Here we compared T-cell functions including the number of circulating CD3+T cells,in vitroresponses to mitogens, T-cell receptor (TCR) repertoire, TCR excision circles (TREC) levels, and regulatory T cells (Tregs) enumeration in several immunodeficinecy subtypes, clinically presenting with nonreactive residual cells (MHC-II deficiency) or reactive cells. The latter includes patients with autoreactive clonal expanded T cell and patients with alloreactive transplacentally maternal T cells.Results. MHC-II deficient patients had slightly reduced T-cell function, normal TRECs, TCR repertoires, and normal Tregs enumeration. In contrast, patients with reactive T cells exhibited poor T-cell differentiation and activity. While the autoreactive cells displayed significantly reduced Tregs numbers, the alloreactive transplacentally acquired maternal lymphocytes had high functional Tregs.Conclusion. SCID patients presenting with circulating T cells show different patterns of T-cell activity and regulatory T cells enumeration that dictates the immunodeficient and autoimmune manifestations. We suggest that a high-tolerance capacity of the alloreactive transplacentally acquired maternal lymphocytes represents a toleration advantage, yet still associated with severe immunodeficiency.

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Silymarin Restores Regulatory T Cells (Tregs) Function in Multiple Sclerosis (MS) Patients In Vitro

Inflammation ◽

10.1007/s10753-019-00980-9 ◽

2019 ◽

Vol 42 (4) ◽

pp. 1203-1214 ◽

Cited By ~ 2

Author(s):

Maryam Shariati ◽

Vahid Shaygannejad ◽

Faezeh Abbasirad ◽

Fahimeh Hosseininasab ◽

Mohammad Kazemi ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

Regulatory T Cells

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Modulation of Tetraspanin 32 (TSPAN32) Expression in T Cell-Mediated Immune Responses and in Multiple Sclerosis

International Journal of Molecular Sciences ◽

10.3390/ijms20184323 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4323 ◽

Cited By ~ 10

Author(s):

Salvo Danilo Lombardo ◽

Emanuela Mazzon ◽

Maria Sofia Basile ◽

Giorgia Campo ◽

Federica Corsico ◽

...

Keyword(s):

Multiple Sclerosis ◽

T Cells ◽

T Cell ◽

Immune Responses ◽

Cancer Metastasis ◽

Treg Cells ◽

T Helper ◽

Autoimmune Encephalomyelitis ◽

Healthy Donors

Tetraspanins are a conserved family of proteins involved in a number of biological processes including, cell–cell interactions, fertility, cancer metastasis and immune responses. It has previously been shown that TSPAN32 knockout mice have normal hemopoiesis and B-cell responses, but hyperproliferative T cells. Here, we show that TSPAN32 is expressed at higher levels in the lymphoid lineage as compared to myeloid cells. In vitro activation of T helper cells via anti-CD3/CD28 is associated with a significant downregulation of TSPAN32. Interestingly, engagement of CD3 is sufficient to modulate TSPAN32 expression, and its effect is potentiated by costimulation with anti-CD28, but not anti-CTLA4, -ICOS nor -PD1. Accordingly, we measured the transcriptomic levels of TSPAN32 in polarized T cells under Th1 and Th2 conditions and TSPAN32 resulted significantly reduced as compared with unstimulated cells. On the other hand, in Treg cells, TSPAN32 underwent minor changes upon activation. The in vitro data were finally translated into the context of multiple sclerosis (MS). Encephalitogenic T cells from Myelin Oligodendrocyte Glycoprotein (MOG)-Induced Experimental Autoimmune Encephalomyelitis (EAE) mice showed significantly lower levels of TSPAN32 and increased levels of CD9, CD53, CD82 and CD151. Similarly, in vitro-activated circulating CD4 T cells from MS patients showed lower levels of TSPAN32 as compared with cells from healthy donors. Overall, these data suggest an immunoregulatory role for TSPAN32 in T helper immune response and may represent a target of future immunoregulatory therapies for T cell-mediated autoimmune diseases.

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Suppression of NK Cell-Mediated Bone Marrow Cell Rejection by CD4+CD25+ Regulatory T Cells: Linkage of Adaptive to Innate Responses.

Blood ◽

10.1182/blood.v106.11.2195.2195 ◽

2005 ◽

Vol 106 (11) ◽

pp. 2195-2195

Author(s):

William J. Murphy ◽

Isabel Bareo ◽

Alan M. Hanash ◽

Lisbeth A. Welniak ◽

Kai Sun ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Regulatory T Cells ◽

Cell Function ◽

Nk Cell ◽

Marrow Cell ◽

Poly I:C ◽

Hybrid Resistance

Abstract While a link between the innate to adaptive immune system has been established, studies demonstrating direct effects of T cells in regulating Natural Killer (NK) cell function have been lacking. Naturally occurring CD4+CD25+ regulatory T cells (Tregs) have been shown to potently inhibit adaptive responses by T cells. We therefore investigated whether Tregs could affect NK cell function in vivo. Using a bone marrow transplantation (BMT) model of hybrid resistance, in which parental (H2d) marrow grafts are rejected by the NK cells of the F1 recipients (H2bxd), we demonstrate that the in vivo removal of host Tregs significantly enhances NK-cell mediated BM rejection. This heightened rejection was mediated by the specific NK cell Ly-49+ subset previously demonstrated to reject the BMC in this donor/host pairing. The depletion of Tregs could also further increase rejection already enhanced by treating recipients with the NK cell activator, poly I:C. Although splenic NK cell numbers were not significantly altered, increased splenic NK in vitro cytotoxic activity was observed from the recovered cells. The regulatory role of Tregs was confirmed in adoptive transfer studies in which transferred CD4+CD25+ Tregs resulted in abrogation of NK cell-mediated hybrid resistance. Thus, Tregs can potently inhibit NK cell function in vivo and their depletion may have therapeutic ramifications with NK cell function in BMT and cancer therapy.

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CD4+ CD25+ Regulatory T Cells Control T Helper Cell Type 1 Responses to Foreign Antigens Induced by Mature Dendritic Cells In Vivo

Journal of Experimental Medicine ◽

10.1084/jem.20030654 ◽

2003 ◽

Vol 198 (2) ◽

pp. 259-266 ◽

Cited By ~ 169

Author(s):

Guillaume Oldenhove ◽

Magali de Heusch ◽

Georgette Urbain-Vansanten ◽

Jacques Urbain ◽

Charlie Maliszewski ◽

...

Keyword(s):

T Cells ◽

Dendritic Cells ◽

Regulatory T Cells ◽

Immune Responses ◽

Peripheral Tolerance ◽

T Helper Cell ◽

Helper Cell ◽

T Helper

Recent evidence suggests that in addition to their well known stimulatory properties, dendritic cells (DCs) may play a major role in peripheral tolerance. It is still unclear whether a distinct subtype or activation status of DC exists that promotes the differentiation of suppressor rather than effector T cells from naive precursors. In this work, we tested whether the naturally occurring CD4+ CD25+ regulatory T cells (Treg) may control immune responses induced by DCs in vivo. We characterized the immune response induced by adoptive transfer of antigen-pulsed mature DCs into mice depleted or not of CD25+ cells. We found that the development of major histocompatibility complex class I and II–restricted interferon γ–producing cells was consistently enhanced in the absence of Treg. By contrast, T helper cell (Th)2 priming was down-regulated in the same conditions. This regulation was independent of interleukin 10 production by DCs. Of note, splenic DCs incubated in vitro with Toll-like receptor ligands (lipopolysaccharide or CpG) activated immune responses that remained sensitive to Treg function. Our data further show that mature DCs induced higher cytotoxic activity in CD25-depleted recipients as compared with untreated hosts. We conclude that Treg naturally exert a negative feedback mechanism on Th1-type responses induced by mature DCs in vivo.

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Fast and Efficient Genome Editing of Human FOXP3+ Regulatory T Cells

Frontiers in Immunology ◽

10.3389/fimmu.2021.655122 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lauren Van Zeebroeck ◽

Rebeca Arroyo Hornero ◽

Beatriz F. Côrte-Real ◽

Ibrahim Hamad ◽

Torsten B. Meissner ◽

...

Keyword(s):

T Cells ◽

Regulatory T Cells ◽

Genome Editing ◽

Therapeutic Target ◽

Peripheral Tolerance ◽

Immune Homeostasis ◽

Cell Integrity ◽

Potential Therapeutic Target ◽

Functional Assays

FOXP3+ regulatory T cells (Tregs) are central for maintaining peripheral tolerance and immune homeostasis. Because of their immunosuppressive characteristics, Tregs are a potential therapeutic target in various diseases such as autoimmunity, transplantation and infectious diseases like COVID-19. Numerous studies are currently exploring the potential of adoptive Treg therapy in different disease settings and novel genome editing techniques like CRISPR/Cas will likely widen possibilities to strengthen its efficacy. However, robust and expeditious protocols for genome editing of human Tregs are limited. Here, we describe a rapid and effective protocol for reaching high genome editing efficiencies in human Tregs without compromising cell integrity, suitable for potential therapeutic applications. By deletion of IL2RA encoding for IL-2 receptor α-chain (CD25) in Tregs, we demonstrated the applicability of the method for downstream functional assays and highlighted the importance for CD25 for in vitro suppressive function of human Tregs. Moreover, deletion of IL6RA (CD126) in human Tregs elicits cytokine unresponsiveness and thus may prevent IL-6-mediated instability of Tregs, making it an attractive target to potentially boost functionality in settings of adoptive Treg therapies to contain overreaching inflammation or autoimmunity. Thus, our rapid and efficient protocol for genome editing in human Tregs may advance possibilities for Treg-based cellular therapies.

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Vitro Culture and Regulation Of Osteoblasts and Cellular Immunity Function In Multiple Myeloma patients

Blood ◽

10.1182/blood.v122.21.5329.5329 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5329-5329

Author(s):

Rong Fu ◽

Shan Gao ◽

Zonghong Shao

Keyword(s):

Multiple Myeloma ◽

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Cellular Immunity ◽

Normal Subjects ◽

Biological Characteristics ◽

Osteogenic Potential ◽

Normal Controls

Abstract Objective To investigate the biological characteristics of osteoblasts（OBs) cultured in vitro from bone marrow（BM) of multiple myeloma(MM) patients and to explore their generation and osteogenic potential. Then the affects by some factors such as bortezomib and MM patient serum on the OBs were observed. To explore the cellular immunity changes and the relationship between OBs and the immunity in MM. Methods OBs from BM of MM patients were cultured in vitro. The generation and osteogenic potential of OBs from MM patients and normal subjects were compared. The changes of their osteogenic potential and biological characteristics were observed. The antigens (CD34、CD138、CD45) on OBs and the quantities of T cell subsets，Dendritic cells(DC)，effective T cells、regulatory T cells and helper T cells (Th）were examined with flow cytometry assay. And then correlation was analyzed between OBs and the immunity. The levels of IL-7 were measured with ELISA. The BMP2 mRNAs were measured by RT-PCR. Results OBs from BM of MM patients could be cultured in vitro. The quantity of OBs from MM patients was less than normal subjects. There were calcium depositions in both groups after cultured for 4weeks culture. But the depositions of MM patients was less than that of normal controls. The OBs cultured with MM patient serum were less than those without patient serum. Bortezomib increased those from MM patients. CD138, CD45, CD34 were not detected on the cultured cells. The ratio of CD4+/CD8+、DC1/DC2、CD8+CD25+/CD3+T were reduced, that of helper T cell (Th1/Th2) was significantly decreased; the percentages of CD4+CD25+/ CD3+T and CD4+CD25+CD127low/CD4+T were significantly higher. Some of them were correlated with the quantity of OBs. The level of IL-7 in serum of MM patients was higher than that of normal controls. The expression of BMP2 mRNA was seen in the normal OBs and MM patients’ OBs culured with bortezomib, but not be seen in those without bortezomib. Conclusions OBs could be cultured in vitro from BM of MM patients. The proliferation and osteogenic potential of OBs from MM patients were decreased. Bortezomib was a positive regulatory of OBs and MM patient serum was a negative one. They both could affect the proliferation and osteogenic potential of OBs. There were down-regulations of quantity and function of T cell subgroup, DC cell, helper T cell, effector T cell while the regulatory T cells relatively raised. Predominantly of them were correlated with the quantity of OBs. Disclosures: No relevant conflicts of interest to declare.

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