Faculty Opinions recommendation of The macrophage F4/80 receptor is required for the induction of antigen-specific efferent regulatory T cells in peripheral tolerance.

2005 ◽  
Author(s):  
Richard Williams
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Peripheral Tolerance

scholarly journals Reduced Follicular Regulatory T Cells in Spleen and Pancreatic Lymph Nodes of Patients With Type 1 Diabetes

2021 ◽  
Author(s):  
Andrea Vecchione ◽  
Tatiana Jofra ◽  
Jolanda Gerosa ◽  
Kimberly Shankwitz ◽  
Roberta Di Fonte ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Lymph Nodes ◽  
Organ Donor ◽  
Peripheral Tolerance ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Pancreatic Lymph Nodes ◽  
Cell Alterations ◽  
Humoral Tolerance

In the attempt to understand the origin of autoantibody (AAb) production in patients with and at-risk for T1D, multiple studies have analyzed and reported alterations in follicular helper T cells (Tfh) in presymptomatic AAb-positive subjects and patients with T1D. Yet, it is still not clear whether the regulatory counterpart of Tfh cells, represented by follicular regulatory T cells (Tfr), is similarly altered. To address this question, we performed analyses in peripheral blood, spleen and pancreatic lymph nodes (PLN) of organ donor subjects with T1D. Blood analyses were also performed in living AAb-negative and -positive subjects. While negligible differences in the frequency and phenotype of blood Tfr cells were observed between T1D, AAb-negative and AAb-positive adult subjects, the frequency of Tfr cells was significantly reduced in spleen and PLN of T1D as compared to non-diabetic controls. Furthermore, adoptive transfer of Tfr cells delayed disease development in a mouse model of T1D, a finding that could indicate that Tfr cells play an important role in peripheral tolerance and regulation of autoreactive Tfh cells. Together, our findings provide evidence of Tfr cell alterations within disease-relevant tissues in patients with T1D suggesting a role for Tfr cells in defective humoral tolerance and disease pathogenesis.

scholarly journals Platelet Gene Therapy Promotes Targeted Peripheral Tolerance by Clonal Deletion and Induction of Antigen-Specific Regulatory T Cells

2018 ◽  
Vol 9 ◽  
Author(s):  
Xiaofeng Luo ◽  
Juan Chen ◽  
Jocelyn A. Schroeder ◽  
Kenneth P. Allen ◽  
Christina K. Baumgartner ◽  
...  
Keyword(s):  
Gene Therapy ◽  
T Cells ◽  
Regulatory T Cells ◽  
Peripheral Tolerance ◽  
Clonal Deletion

Double Negative T Cells Influence TCR VB Variablity to Induce Allotolerance.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 759-759
Author(s):  
Zachariah A. McIver ◽  
Marcin Wlodarski ◽  
Jennifer Powers ◽  
Christine O’Keefe ◽  
Tao Jin ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Peripheral Tolerance ◽  
Double Negative ◽  
Clonal Deletion ◽  
Tcr Repertoire ◽  
Double Negative T Cells

Abstract Immune alloresponsiveness following allogeneic HSCT is influenced by the dynamics of immune reconstitution and development of allotolerance. In general, tolerance is induced by thymic clonal deletion (central) and apoptosis or suppression of alloresponsive lymphocytes by regulatory T cells in the periphery. We have recently demonstrated that the size of the TCR repertoire within the CD4 and CD8 compartments can be assessed using VB spectrum by flow cytometry, and expansions/losses of individual TCR VB families can be used as a surrogate marker of TCR variability. (Exp. Hem.32: 1010–1022; Br. J. Haematol.129:411–419). Additionally, regulatory T cells can also impact the clonal contractions and expansions within the TCR VB repertoire. Various types of regulatory T cells have been described including CD4+CD25+, CD8+, NK T−cells, and CD3+CD4/CD8− double negative T cells (DN Tregs). In our current study we investigated the role of DN Tregs on the restoration of immune repertoire diversity. We hypothesized that alloresponsiveness clinically detected as a manifestation of GvHD may be associated with oligoclonal T−cell expansions, and in this context decreased numbers of regulatory T cells suggest deficient tolerizing function by regulatory T cells including DN Tregs. Here we studied a cohort of 60 HSCT recipients (AML, CML, CLL, NHL, AA, and PV), of which 25 patients received matched unrelated donor grafts and 35 received matched sibling donor grafts. Blood was sampled between 2003–2006 at monthly intervals after HSCT, and flow cytometry for TCR repertoire in CD4 and CD8 cells as well as the numbers of DN cells were recorded. Additionally, separate samples were collected for measurement of chimerism and were included in analysis when donor lymphoid chimerism was > 60%. A subset analysis was performed based on the presence/absence of GvHD. For the 27/60 (45%) patients with episodes of GvHD, results were obtained at the time of diagnosis of GvHD (grade > 2), while for patients in whom notable GvHD was not captured, the steady−state values at corresponding times were used for analysis. For all patients serial evaluations were available. For the purpose of this study, significant VB expansions/contractions were defined as +/− 2 standard deviation over the average VB family size. Using Cox proportional hazards analysis to identify univariate risk factors for GVHD, CD8 VB TCR contractions > 14 VB families (58.3% contraction of entire CD4 VB repertoire) constituted a strong indicator for increased risk (HR=7.61, p=0.011). This observation is consistent with the fact that oligoclonality of alloreactive T cell clones is frequently accompanied by a significant contraction/loss of remaining VB families and may herald heightened alloresponsiveness as a manifestation of GvHD. Estimation for correlation by Pearson’s correlation coefficient also demonstrated that percentage of DN cells strongly correlated with a normalization of CD4 VB TCR repertoire (lower number of expansions; N=57, R= −0.51, p=0.027), supporting our hypothesis that DN cells participate in peripheral tolerance and suppress proliferative, alloresponsive CD4 clones. In summary, our results further characterize TCR variability post HSCT and define the role of DN cells in the induction of allotolerance.

Cell-Based Immunotherapy with Different Subsets of Tolerogenic Dendritic Cell in Idiopathic Thrombocytopenic Purpura.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3408-3408
Author(s):  
Xiao-Lin Zhang ◽  
Jun Peng ◽  
Shu-Qian Xu ◽  
Xin-Guang Liu ◽  
Yuan Yu ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Idiopathic Thrombocytopenic Purpura ◽  
Peripheral Tolerance ◽  
Platelet Glycoprotein ◽  
Autoantibody Production ◽  
Autoreactive T Cells ◽  
Thrombocytopenic Purpura ◽  
Autoreactive T Cell ◽  
Tolerogenic Dcs

Abstract There is growing evidence that tolerogenic dendritic cells (DCs) play an important role in maintaining peripheral tolerance through the induction of anergic or regulatory T cells. However, in humans, little is known about the ability of tolerogenic DCs to induce tolerance to autoantigens in autoimmune patients. Idiopathic thrombocytopenic purpura (ITP) is an immune-mediated disease in which platelets are destroyed by antiplatelet autoantibodies. Here, we explored in vitro the ability of four subsets of tolerogenic DCs (i.e., immature DCs (imDCs), IL-10-modulated DCs (IL-10-DCs), vasoactive intestinal peptide-modulated DCs (VIP-DCs) or plasmacytoid DCs (pDCs)) derived from patients with ITP, to induce an anergic state or regulatory T cells in autologous platelet glycoprotein (GP)-specific T cells. GPIIb/IIIa-reactive T cells were preincubated with GPIIb/IIIa-loaded imDCs, IL- 10-DCs, pDCs or VIP-DCs, and then rechallenged with autologous mature DCs (mDCs) in the presence of GPIIb/IIIa. Only when T cells were cultured with GPIIb/IIIa-loaded VIP-DCs in primary incubation, inhibited proliferation of GPIIb/IIIa-reactive T cells could be observed at rechallenge with GPIIb/IIIa-loaded mDCs. The anergic state of VIPDC- primed GPIIb/IIIa-reactive T cells could be reversed when rechallenged with GPIIb/ IIIa-loaded mDCs in the presence of a high concentration of exogenous IL-2. Meanwhile, GPIIb/IIIa-reactive T cells were also cultured with VIP-DCs loaded with tetanus toxoid (TT). In contrast to T cells pretreated with GPIIb/IIIa-loaded VIP-DCs, GPIIb/IIIareactive T cells pretreated with TT-loaded VIP-DCs proliferated when rechallenged with GPIIb/IIIa-loaded mDCs, which demonstrated that the induced anergy of autoreactive T cells is antigen specific. Additionally, functional analysis showed that VIP-DC-modulated T cells could not suppress the proliferation of newly induced GPIIb/IIIa-reactive T cells when cocultured with GPIIb/IIIa-loaded mDCs. These results indicated that VIP-DCs could induce autoreactive T cells anergic but not functionally suppressive. Moreover, we found that coculture of VIP-DCs with autologous PBMCs resulted in reduced production of anti-GPIIb/IIIa antibodies, suggesting that GPIIb/IIIa-reactive T cells lost their helper function for inducing autoantibody production by B cells. In contrast, reduced antibody production could not be found when autologous PBMCs were cocultured with imDCs, IL-10-DCs or pDCs. In conclusion, our studies revealed the therapeutic potential of VIPDCs, compared with imDCs, IL-10-DCs or pDCs, to induce autoreactive T-cell anergy to GP antigens, which would in turn facilitate the reestablishment of autoantigen-specific tolerance in patients with ITP.

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

2003 ◽  
Vol 198 (2) ◽  
pp. 259-266 ◽  
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.

scholarly journals Active Translation Control of CD4 T Cell Activation by Regulatory T Cells

2021 ◽  
Author(s):  
Lomon So ◽  
Kazushige Obata-Ninomiya ◽  
Alex Hu ◽  
Virginia Muir ◽  
Ayako Takamori ◽  
...  
Keyword(s):  
T Cells ◽  
Protein Synthesis ◽  
Regulatory T Cells ◽  
Cell Activation ◽  
Peripheral Tolerance ◽  
Transcriptional Level ◽  
Translation Control ◽  
Teff Cell ◽  
Protein Synthesis Machinery ◽  
Global Protein Synthesis

Increased protein synthesis is a hallmark of lymphocyte activation. Regulatory T cells (Tregs) suppress the activation and subsequent effector functions of CD4 effector T cells (Teff). Molecular mechanisms that enforce suppression on CD4 Teff cell function are unclear. Control of CD4 Teff cell activation by Tregs has largely been defined at the transcriptional level, which does not reflect changes in post-transcriptional control. We found that Tregs suppressed activation-induced global protein synthesis in CD4 Teff cells prior to cell division. We analyzed genome-wide changes in the transcriptome and translatome of activated CD4 Teff cells using two independent approaches. We show that mRNAs encoding for the protein synthesis machinery are regulated at the level of translation in activated Teff cells. Strikingly, Tregs suppressed global protein synthesis of CD4 Teff cells by specifically inhibiting mRNAs of the translation machinery at the level of mTORC1-mediated translation control. Lastly, we found that the RNA helicase eIF4A inhibitor rocaglamide A (RocA) can suppress CD4 Teff activation in vitro to alleviate inflammatory CD4 Teff activation caused by acute Treg depletion in vivo. These data provide evidence that peripheral tolerance is enforced by Tregs, mediated by IL-10, through mRNA translational control in CD4 Teff cells. Therefore, therapeutic targeting of the protein synthesis machinery can mitigate inflammatory responses invoked by Treg loss of function.

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

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.

REGULATORY T CELLS MAINTAIN PERIPHERAL TOLERANCE TO ISLET ALLOGRAFTS INDUCED BY INTRATHYMIC INJECTION OF MHC CLASS I ALLOPEPTIDES

1998 ◽  
Vol 66 (8) ◽  
pp. S31
Author(s):  
D V Saborio ◽  
N C Chowdhury ◽  
M X Jin ◽  
M H Sayegh ◽  
A Chandraker ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Mhc Class I ◽  
Peripheral Tolerance ◽  
Class I ◽  
Islet Allografts ◽  
Intrathymic Injection

scholarly journals Regulatory Role of CD4+ T Cells in Myocarditis

2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Daria Vdovenko ◽  
Urs Eriksson
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Young Patients ◽  
Peripheral Tolerance ◽  
T Cell Subsets ◽  
High Plasticity ◽  
Clonal Deletion ◽  
Effector T Cell

Myocarditis is an important cause of heart failure in young patients. Autoreactive, most often, infection-triggered CD4+ T cells were confirmed to be critical for myocarditis induction. Due to a defect in clonal deletion of heart-reactive CD4+ T cells in the thymus of mice and humans, significant numbers of heart-specific autoreactive CD4+ T cells circulate in the blood. Normally, regulatory T cells maintain peripheral tolerance and prevent spontaneous myocarditis development. In the presence of tissue damage and innate immune activation, however, activated self-antigen-loaded dendritic cells promote CD4+ effector T cell expansion and myocarditis. So far, a direct pathogenic role has been described for both activated Th17 and Th1 effector CD4+ T cell subsets, though Th1 effector T cell-derived interferon-gamma was shown to limit myocarditis severity and prevent transition to inflammatory dilated cardiomyopathy. Interestingly, recent observations point out that various CD4+ T cell subsets demonstrate high plasticity in maintaining immune homeostasis and modulating disease phenotypes in myocarditis. These subsets include Th1 and Th17 effector cells and regulatory T cells, despite the fact that there are still sparse and controversial data on the specific role of FOXP3-expressing Treg in myocarditis. Understanding the specific roles of these T cell populations at different stages of the disease progression might provide a key for the development of successful therapeutic strategies.

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