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 Regulatory T cells in acute and chronic kidney diseases

2018 ◽  
Vol 314 (5) ◽  
pp. F679-F698 ◽  
Author(s):  
Rahul Sharma ◽  
Gilbert R. Kinsey
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cell Activation ◽  
Cell Function ◽  
Immune Cell ◽  
Inflammatory Diseases ◽  
Kidney Diseases ◽  
Peripheral Tolerance ◽  
Autoimmune And Inflammatory Diseases

Foxp3-expressing CD4+ regulatory T cells (Tregs) make up one subset of the helper T cells (Th) and are one of the major mechanisms of peripheral tolerance. Tregs prevent abnormal activation of the immune system throughout the lifespan, thus protecting from autoimmune and inflammatory diseases. Recent studies have elucidated the role of Tregs beyond autoimmunity. Tregs play important functions in controlling not only innate and adaptive immune cell activation, but also regulate nonimmune cell function during insults and injury. Inflammation contributes to a multitude of acute and chronic diseases affecting the kidneys. This review examines the role of Tregs in pathogenesis of renal inflammatory diseases and explores the approaches for enhancing Tregs for prevention and therapy of renal inflammation.

Deciphering the role of TRIB1 in regulatory T-cells

2015 ◽  
Vol 43 (5) ◽  
pp. 1075-1078 ◽  
Author(s):  
Richard Danger ◽  
Emilie Dugast ◽  
Faouzi Braza ◽  
Sophie Conchon ◽  
Sophie Brouard
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Molecular Mechanisms ◽  
Peripheral Tolerance ◽  
Antibody Mediated Rejection ◽  
Screening Experiments ◽  
Cluster Of Differentiation

The role of regulatory T-cells (Tregs) is crucial to maintain immune homoeostasis by controlling peripheral tolerance. A better understanding in the molecular mechanisms involved in the biology of these Tregs could improve their expansion and selection to treat immune-related diseases, achieve immunosuppression-free organ transplantation and to specifically target them in cancer. We reported on the overexpression of tribbles-1 (TRIB1) in Tregs compared with their counterpart naive T-cells and that TRIB1 interacts with the master molecule of Tregs, forkhead box P3 (FOXP3), a transcription factor essential for Treg suppressive activity. We demonstrated that these two molecules interact together in the nucleus of Tregs and TRIB1 overexpression is associated with a decrease in their proliferative capacities. Since TRIB1 was reported to be overexpressed in the blood of renal transplanted patients with chronic antibody-mediated rejection (CAMR), altogether, these results suggest TRIB1 could be linked to the decrease proportion of Tregs in patients exhibiting CAMR and a key player in Tregs through its FOXP3 interaction. In addition, yeast two-hybrid screening experiments highlighted that TRIB1 potentially interacts with molecules playing roles in intracellular events following T-cell activation and particularly cluster of differentiation (CD)4+ T-cells. This suggests still non explored potential links between TRIB1 in Tregs. Our goal is thus to decipher the role of TRIB1 in the Treg biology, notably in pathways known to involved its partner and main transcriptional factor of Tregs, FOXP3 and to determine the role of TRIB1 in immune pathologies.

scholarly journals Foxp3+ Regulatory T Cells Delay Expulsion of Intestinal Nematodes by Suppression of IL-9-Driven Mast Cell Activation in BALB/c but Not in C57BL/6 Mice

2014 ◽  
Vol 10 (2) ◽  
pp. e1003913 ◽  
Author(s):  
Birte Blankenhaus ◽  
Martina Reitz ◽  
Yannick Brenz ◽  
Marie-Luise Eschbach ◽  
Wiebke Hartmann ◽  
...  
Keyword(s):  
T Cells ◽  
Mast Cell ◽  
Regulatory T Cells ◽  
Cell Activation ◽  
Mast Cell Activation

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 Fas/FasL Signaling Regulates CD8 Expression During Exposure to Self-Antigens

2021 ◽  
Vol 12 ◽  
Author(s):  
Giovanna Flores-Mendoza ◽  
Noé Rodríguez-Rodríguez ◽  
Rosa M. Rubio ◽  
Iris K. Madera-Salcedo ◽  
Florencia Rosetti ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell Activation ◽  
Cell Activation ◽  
Peripheral Tolerance ◽  
Tolerance Mechanism ◽  
Genetic Deficiency ◽  
Self Antigen ◽  
Insight Into ◽  
Self Antigens

Activation of self-reactive CD8+ T cells induces a peripheral tolerance mechanism that involves loss of CD8 expression. Because genetic deficiency of Fas and Fasl causes the accumulation of double-negative (DN; CD3+ TCR-αβ+ CD4- CD8-) T cells that have been proposed to derive from CD8+ cells, we decided to explore the role of Fas and FasL in self-antigen-induced CD8 downregulation. To this end, we quantified Fas and FasL induction by different stimuli and analyzed the effects of Fas/FasL deficiency during a protective immune response and after exposure to self-antigens. Our data describes how Fas and FasL upregulation differs depending on the setting of CD8 T cell activation and demonstrates that Fas/FasL signaling maintains CD8 expression during repetitive antigen stimulation and following self-antigen encounter. Together, our results reveal an unexpected role of Fas/FasL signaling and offer a new insight into the role of these molecules in the regulation of immune tolerance.

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

scholarly journals IL10-Deficiency in CD4+ T Cells Exacerbates the IFNγ and IL17 Response During Bacteria Induced Colitis

2015 ◽  
Vol 36 (4) ◽  
pp. 1259-1273 ◽  
Author(s):  
Virginia Seiffart ◽  
Julia Zoeller ◽  
Robert Klopfleisch ◽  
Munisch Wadwa ◽  
Wiebke Hansen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Intestinal Inflammation ◽  
Cd4 T Cell ◽  
Intestinal Homeostasis ◽  
Crypt Hyperplasia

Background/Aims: IL10 is a key inhibitor of effector T cell activation and a mediator of intestinal homeostasis. In addition, IL10 has emerged as a key immunoregulator during infection with various pathogens, ameliorating the excessive T-cell responses that are responsible for much of the immunopathology associated with the infection. Because IL10 plays an important role in both intestinal homeostasis and infection, we studied the function of IL10 in infection-associated intestinal inflammation. Methods: Wildtype mice and mice deficient in CD4+ T cell-derived or regulatory T cells-derived IL10 were infected with the enteric pathogen Citrobacter (C.) rodentium and analyzed for the specific immune response and pathogloy in the colon. Results: We found that IL10 expression is upregulated in colonic tissue after infection with C. rodentium, especially in CD4+ T cells, macrophages and dendritic cells. Whereas the deletion of IL10 in regulatory T cells had no effect on C. rodentium induced colitis, infection of mice deficient in CD4+ T cell-derived IL10 exhibited faster clearance of the bacterial burden but worse colitis, crypt hyperplasia, and pathology than did WT mice. In addition, the depletion of CD4+ T cell-derived IL10 in infected animals was accompanied by an accelerated IFNγ and IL17 response in the colon. Conclusion: Thus, we conclude that CD4+ T cell-derived IL10 is strongly involved in the control of C. rodentium-induced colitis. Interference with this network could have implications for the treatment of infection-associated intestinal inflammation.

scholarly journals Murine regulatory T cells differ from conventional T cells in resisting the CTLA-4 reversal of TCR stop-signal

Blood ◽  
2012 ◽  
Vol 120 (23) ◽  
pp. 4560-4570 ◽  
Author(s):  
Yuning Lu ◽  
Helga Schneider ◽  
Christopher E. Rudd
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mechanistic Explanation ◽  
Stop Signal ◽  
Detectable Effect ◽  
First Time

Abstract CTLA-4 inhibits T-cell activation and protects against the development of autoimmunity. We and others previously showed that the coreceptor can induce T-cell motility and shorten dwell times with dendritic cells (DCs). However, it has been unclear whether this property of CTLA-4 affects both conventional T cells (Tconvs) and regulatory T cells (Tregs). Here, we report that CTLA-4 had significantly more potent effects on the motility and contact times of Tconvs than Tregs. This was shown firstly by anti–CTLA-4 reversal of the anti-CD3 stop-signal on FoxP3-negative cells at concentrations that had no effect on FoxP3-positive Tregs. Secondly, the presence of CTLA-4 reduced the contact times of DO11.10 x CD4+CD25− Tconvs, but not DO11.10 x CD4+CD25+ Tregs, with OVA peptide presenting DCs in lymph nodes. Thirdly, blocking of CTLA-4 with anti–CTLA-4 Fab increased the contact times of Tconvs, but not Tregs with DCs. By contrast, the presence of CD28 in a comparison of Cd28−/− and Cd28+/+ DO11.10 T cells had no detectable effect on the contact times of either Tconvs or Tregs with DCs. Our findings identify for the first time a mechanistic explanation to account for CTLA-4–negative regulation of Tconv cells but not Tregs in immune responses.

Sign in / Sign up

Export Citation Format

Share Document