scholarly journals Regulatory T cells suppress the formation of super-effector CD8 T cells by limiting IL-2

2021 ◽  
Author(s):  
Oksana Tsyklauri ◽  
Tereza Chadimova ◽  
Veronika Niederlova ◽  
Jirina Kovarova ◽  
Juraj Michalik ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cd8 T Cells ◽  
Autoimmune Diabetes ◽  
Effector T Cells ◽  
Activated T Cells ◽  
Promote Tumor Growth ◽  
Self Tolerance ◽  
Suppression Mechanism ◽  
Cytotoxic Molecules

Regulatory T cells (Tregs) are indispensable for maintaining self-tolerance by suppressing conventional T cells. On the other hand, Tregs may promote tumor growth by inhibiting anti-cancer immunity. In this study, we identified that Tregs increase the quorum of self-reactive CD8+ T cells required for the induction of experimental autoimmune diabetes. Their major suppression mechanism is limiting available IL-2, a key cytokine for activated T cells. Specifically, Tregs inhibit the formation of a previously uncharacterized subset of antigen-stimulated CD8+ T cells. Since these T cells express high levels of IL-7 receptor and cytotoxic molecules (KLRK1, GZMB), and show superior cell killing abilities, we call them super-effector T cells. The administration of agonistic IL-2 immunocomplexes phenocopies the absence of Tregs, i.e., it induces super-effector T cells, promotes autoimmunity, and enhances anti-tumor responses. Counterparts of super-effector T cells were found in the human blood, revealing them as a potential target for immunotherapy.

scholarly journals Sustained suppression by Foxp3+ regulatory T cells is vital for infectious transplantation tolerance

2011 ◽  
Vol 208 (10) ◽  
pp. 2043-2053 ◽  
Author(s):  
Adrian R. Kendal ◽  
Ye Chen ◽  
Frederico S. Regateiro ◽  
Jianbo Ma ◽  
Elizabeth Adams ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Tissue Damage ◽  
Paradigm Shift ◽  
Effector T Cells ◽  
Transplantation Tolerance ◽  
Self Tolerance ◽  
Infectious Tolerance ◽  
First Time

A paradigm shift in immunology has been the recent discovery of regulatory T cells (T reg cells), of which CD4+Foxp3+ cells are proven as essential to self-tolerance. Using transgenic B6.Foxp3hCD2 mice to isolate and ablate Foxp3+ T reg cells with an anti-hCD2 antibody, we show for the first time that CD4+Foxp3+ cells are crucial for infectious tolerance induced by nonablative anti–T cell antibodies. In tolerant animals, Foxp3+ T reg cells are constantly required to suppress effector T cells still capable of causing tissue damage. Tolerated tissue contains T cells that are capable of rejecting it, but are prevented from doing so by therapeutically induced Foxp3+ T reg cells. Finally, Foxp3+ cells have been confirmed as the critical missing link through which infectious tolerance operates in vivo. Peripherally induced Foxp3+ cells sustain tolerance by converting naive T cells into the next generation of Foxp3+ cells. Empowering Foxp3+ regulatory T cells in vivo offers a tractable route to avoid and correct tissue immunopathology.

scholarly journals CTLA4 blockade expands FoxP3+ regulatory and activated effector CD4+ T cells in a dose-dependent fashion

Blood ◽  
2008 ◽  
Vol 112 (4) ◽  
pp. 1175-1183 ◽  
Author(s):  
Brian Kavanagh ◽  
Shaun O'Brien ◽  
David Lee ◽  
Yafei Hou ◽  
Vivian Weinberg ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Cd4 T Cells ◽  
Cytotoxic T Lymphocyte ◽  
Effector T Cells ◽  
Activated T Cells ◽  
Ctla4 Blockade ◽  
Dose Dependent Fashion ◽  
Dose Dependent

AbstractCytotoxic T lymphocyte–associated antigen 4 (CTLA4) delivers inhibitory signals to activated T cells. CTLA4 is constitutively expressed on regulatory CD4+ T cells (Tregs), but its role in these cells remains unclear. CTLA4 blockade has been shown to induce antitumor immunity. In this study, we examined the effects of anti-CTLA4 antibody on the endogenous CD4+ T cells in cancer patients. We show that CTLA4 blockade induces an increase not only in the number of activated effector CD4+ T cells, but also in the number of CD4+ FoxP3+ Tregs. Although the effects were dose-dependent, CD4+ FoxP3+ regulatory T cells could be expanded at lower antibody doses. In contrast, expansion of effector T cells was seen only at the highest dose level studied. Moreover, these expanded CD4+ FoxP3+ regulatory T cells are induced to proliferate with treatment and possess suppressor function. Our results demonstrate that treatment with anti-CTLA4 antibody does not deplete human CD4+ FoxP3+ Tregs in vivo, but rather may mediate its effects through the activation of effector T cells. Our results also suggest that CTLA4 may inhibit Treg proliferation similar to its role on effector T cells. This study is registered at http://www.clinicaltrials.gov/ct2/show/NCT00064129, registry number NCT00064129.

scholarly journals Direct and Indirect Modulation of T Cells by VEGF-A Counteracted by Anti-Angiogenic Treatment

2021 ◽  
Vol 12 ◽  
Author(s):  
Morgane Bourhis ◽  
Juliette Palle ◽  
Isabelle Galy-Fauroux ◽  
Magali Terme
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Cells ◽  
Immune Checkpoint Blockade ◽  
Effector T Cells ◽  
Vascular Endothelial ◽  
Activated T Cells ◽  
Cell Functions ◽  
Endothelial Growth Factor ◽  
The Impact

Vascular endothelial growth factor A is known to play a central role in tumor angiogenesis. Several studies showed that VEGF-A is also an immunosuppressive factor. In tumor-bearing hosts, VEGF-A can modulate immune cells (DC, MDSC, TAM) to induce the accumulation of regulatory T-cells while simultaneously inhibiting T-cell functions. Furthermore, VEGFR-2 expression on activated T-cells and FoxP3high regulatory T-cells also allow a direct effect of VEGF-A. Anti-angiogenic agents targeting VEGF-A/VEGFR contribute to limit tumor-induced immunosuppression. Based on interesting preclinical studies, many clinical trials have been conducted to investigate the efficacy of anti-VEGF-A/VEGFR treatments combined with immune checkpoint blockade leading to the approvement of these associations in different tumor locations. In this review, we focus on the impact of VEGF-A on immune cells especially regulatory and effector T-cells and different therapeutic strategies to restore an antitumor immunity.

scholarly journals Cytocidal macrophages in symbiosis with CD4 and CD8 T cells cause acute diabetes following checkpoint blockade of PD-1 in NOD mice

2020 ◽  
Vol 117 (49) ◽  
pp. 31319-31330
Author(s):  
Hao Hu ◽  
Pavel N. Zakharov ◽  
Orion J. Peterson ◽  
Emil R. Unanue
Keyword(s):  
T Cells ◽  
Cd8 T Cells ◽  
Autoimmune Diabetes ◽  
Critical Role ◽  
Nod Mice ◽  
Checkpoint Blockade ◽  
Cellular Interactions ◽  
Activated T Cells ◽  
Acute Diabetes ◽  
Ifn Γ

Autoimmune diabetes is one of the complications resulting from checkpoint blockade immunotherapy in cancer patients, yet the underlying mechanisms for such an adverse effect are not well understood. Leveraging the diabetes-susceptible nonobese diabetic (NOD) mouse model, we phenocopy the diabetes progression induced by programmed death 1 (PD-1)/PD-L1 blockade and identify a cascade of highly interdependent cellular interactions involving diabetogenic CD4 and CD8 T cells and macrophages. We demonstrate that exhausted CD8 T cells are the major cells that respond to PD-1 blockade producing high levels of IFN-γ. Most importantly, the activated T cells lead to the recruitment of monocyte-derived macrophages that become highly activated when responding to IFN-γ. These macrophages acquire cytocidal activity against β-cells via nitric oxide and induce autoimmune diabetes. Collectively, the data in this study reveal a critical role of macrophages in the PD-1 blockade-induced diabetogenesis, providing new insights for the understanding of checkpoint blockade immunotherapy in cancer and infectious diseases.

scholarly journals Nanoparticles Containing an Insulin–ChgA Hybrid Peptide Protect from Transfer of Autoimmune Diabetes by Shifting the Balance between Effector T Cells and Regulatory T Cells

2019 ◽  
Vol 203 (1) ◽  
pp. 48-57 ◽  
Author(s):  
Braxton L. Jamison ◽  
Tobias Neef ◽  
Andrew Goodspeed ◽  
Brenda Bradley ◽  
Rocky L. Baker ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Autoimmune Diabetes ◽  
Effector T Cells ◽  
Hybrid Peptide

scholarly journals Coexpression of CD25 and CD27 identifies FoxP3+ regulatory T cells in inflamed synovia

2005 ◽  
Vol 201 (11) ◽  
pp. 1793-1803 ◽  
Author(s):  
Claudia R. Ruprecht ◽  
Marco Gattorno ◽  
Francesca Ferlito ◽  
Andrea Gregorio ◽  
Alberto Martini ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Synovial Fluid ◽  
Regulatory T Cells ◽  
Cell Function ◽  
Effector T Cells ◽  
T Cell Proliferation ◽  
Activated T Cells

A better understanding of the role of CD4+CD25+ regulatory T cells in disease pathogenesis should follow from the discovery of reliable markers capable of discriminating regulatory from activated T cells. We report that the CD4+CD25+ population in synovial fluid of juvenile idiopathic arthritis (JIA) patients comprises both regulatory and effector T cells that can be distinguished by expression of CD27. CD4+CD25+CD27+ cells expressed high amounts of FoxP3 (43% of them being FoxP3+), did not produce interleukin (IL)-2, interferon-γ, or tumor necrosis factor, and suppressed T cell proliferation in vitro, being, on a per cell basis, fourfold more potent than the corresponding peripheral blood population. In contrast, CD4+CD25+CD27− cells expressed low amounts of FoxP3, produced effector cytokines and did not suppress T cell proliferation. After in vitro activation and expansion, regulatory but not conventional T cells maintained high expression of CD27. IL-7 and IL-15 were found to be present in synovial fluid of JIA patients and, when added in vitro, abrogated the suppressive activity of regulatory T cells. Together, these results demonstrate that, when used in conjunction with CD25, CD27 is a useful marker to distinguish regulatory from effector T cells in inflamed tissues and suggest that at these sites IL-7 and IL-15 may interfere with regulatory T cell function.

scholarly journals Regulatory T Cells Inhibit T Cell Activity by Downregulating CD137 Ligand via CD137 Trogocytosis

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 353
Author(s):  
Khang Luu ◽  
Mugdha Vijay Patwardhan ◽  
Qun Zeng ◽  
Stina L. Wickström ◽  
Andreas Lundqvist ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Immune Responses ◽  
Costimulatory Molecule ◽  
Cell Activity ◽  
Effector T Cells ◽  
Comparable Data ◽  
Activated T Cells ◽  
Evolutionarily Conserved ◽  
Antigen Presenting

CD137 is a costimulatory molecule expressed on activated T cells. CD137 ligand (CD137L) is expressed by antigen presenting cells (APC), which use the CD137—CD137L system to enhance immune responses. It was, therefore, surprising to discover CD137 expression on regulatory T cells (Treg). The function of CD137 in Treg are controversial. While some studies report that CD137 signalling converts Treg to effector T cells (Teff), other studies find that CD137-expressing Treg display a stronger inhibitory activity than CD137- Treg. Here, we describe that CD137 on Treg binds to CD137L on APC, upon which one of the two molecules is transferred via trogocytosis to the other cell, where CD137—CD137L forms a complex that is internalized and deprives APC of the immune-stimulatory CD137L. Truncated forms of CD137 that lack the cytoplasmic domain of CD137 are also able to downregulate CD137L, demonstrating that CD137 signalling is not required. Comparable data have been obtained with human and murine cells, indicating that this mechanism is evolutionarily conserved. These data describe trogocytosis of CD137 and CD137L as a new mechanism employed by Treg to control immune responses by downregulating the immunostimulatory CD137L on APC.

CD8+ Treg - From Mouse To Man

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3474-3474 ◽  
Author(s):  
Tobias A.W. Holderried ◽  
Hye-Jung Kim ◽  
Philipp A Lang ◽  
Harvey Cantor
Keyword(s):  
T Cells ◽  
Transcription Factor ◽  
T Cell ◽  
Autoimmune Disease ◽  
Regulatory T Cells ◽  
Cd8 T Cells ◽  
Human Homologue ◽  
Cd8 Cells ◽  
Tfh Cells ◽  
Self Tolerance

Abstract T cell-mediated regulation of the immune response to self and foreign antigens is essential to maintain immune homeostasis and prevent autoimmune tissue destruction. The majority of studies addressing this issue, both in mice and humans, have focused on the contribution of CD4+CD25+FOXP3+ regulatory T cells. The contribution of regulatory CD8+ T cells has not been appreciated until recently. Recent studies have identified a small subset of IL-15 dependent CD8+ regulatory T cells (Treg) that is essential for maintenance of self- tolerance and prevention of autoimmune disease in mice. Expression of a triad of cell surface markers – CD44+CD122+Ly49+ – has been used to distinguish and purify CD8+Treg (Kim et al., Nature 2010; Kim et al., PNAS 2011). Here we have defined the human homologue of CD8+ Treg. The Ly49 receptor, identified as a stable surface marker on CD8+ Treg, is a member of a multigenic/multiallelic receptor family recognizing classical MHC class I molecules. The functional homologue of murine Ly49 is the killer cell immunoglobulin-like receptor (KIR). Our analysis has revealed that, while expression of KIR subtype combinations appears to be stochastic and co-expression of these KIR receptors is random, the inhibitory KIR2DL2/3 and KIR3DL1 subtypes are dominantly expressed by human CD3+CD8+ T cells. Similar to murine CD8+ Treg, CD8+ T cells that express KIR2DL2/3 or KIR3DL1 also express CD44 and CD122. Moreover, consistent with murine CD8+ Treg, incubation with IL-15 results in activation and proliferation of KIR+CD8+ T cells that maintain a stable surface phenotype. Gene array analyses in mice has indicated that Helios, a highly conserved zinc finger transcription factor and member of the Ikaros family of transcription factors, is expressed by CD44+CD122+Ly49+ CD8+ Treg. Helios is involved in T cell development and expressed by ∼70% of FoxP3+CD4+ Treg but not by mature B cells, dendritic cells or myeloid cells. Our analyses identified a Helios+ subset in the CD8+ Treg population, which (compared to the Helios- subset) embodies many of the functional characteristics of CD8+ Treg in mice. Co-expression of Helios is also apparent in some KIR+CD8+ T cells in human samples. In mice, we have shown that CD8+ Treg target CD4 TFH cells and thus maintain self-tolerance. In vitro suppression assays revealed that KIR+CD8+ cells but not KIR–CD8+ cells confer inhibitory activity on CD4+CXCR5+ TFHtarget cells in humans. Taken together, our findings implicate KIR+CD8+ cells as the human homologue of murine CD8+ Treg, including expression of transcription factor Helios, responsiveness to IL-15 and suppression of CD4+ TFH cells. Understanding the genetic and biological features of this CD8+ T cell subset in humans opens the possibility of exploiting their regulatory activity for the development of immunotherapy in the context of autoimmune disease and cancer. Disclosures: No relevant conflicts of interest to declare.

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