scholarly journals PD-L1 is expressed on human activated naive effector CD4+ T cells. Regulation by dendritic cells and regulatory CD4+ T cells

PLoS ONE ◽  
2021 ◽  
Vol 16 (11) ◽  
pp. e0260206
Author(s):  
Fabienne Mazerolles ◽  
Frédéric Rieux-Laucat
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
T Lymphocyte ◽  
Cd4 T Cells ◽  
Immunoglobulin Superfamily ◽  
T Cell Proliferation ◽  
Tumour Necrosis Factor Receptor ◽  
Specific Expression

The T cell expression of various co-signalling receptors from the CD28 immunoglobulin superfamily (Inducible T cell co-stimulator (ICOS), Programmed cell death 1(PD-1), cytotoxic T lymphocyte associated protein 4 (CTLA-4), B and T lymphocyte attenuator (BTLA) or from the tumour necrosis factor receptor superfamily (glucocorticoid-induced TNFR family related (GITR), 4-1BB, and CD27), is essential for T cell responses regulation. Other receptors (such as T cell immunoglobulin and mucin domain-containing protein 3, T cell immunoglobulin and T cell immunoglobulin and ITIM domain (TIGIT), and lymphocyte activation gene 3) are also involved in this regulation. Disturbance of the balance between activating and inhibitory signals can induce autoimmunity. We have developed an in vitro assay to simultaneously assess the function of naive CD4+ effector T cells (TEFFs), dendritic cells (DCs) and regulatory T cells (TREGs) and the expression of co-signalling receptors. By running the assay on cells from healthy adult, we investigated the regulation of activated T cell proliferation and phenotypes. We observed that TEFFs activated by DCs mainly expressed BTLA, ICOS and PD-1, whereas activated TREGs mainly expressed TIGIT, ICOS, and CD27. Strikingly, we observed that programmed death-ligand 1 (PD-L1) was significantly expressed on both activated TEFFs and TREGs. Moreover, high PD-L1 expression on activated TEFFs was correlated with a higher index of proliferation. Lastly, and in parallel to the TREG-mediated suppression of TEFF proliferation, we observed the specific modulation of the surface expression of PD-L1 (but not other markers) on activated TEFFs. Our results suggest that the regulation of T cell proliferation is correlated with the specific expression of PD-L1 on activated TEFFs.

scholarly journals Direct Infection of Dendritic Cells during Chronic Viral Infection Suppresses Antiviral T Cell Proliferation and Induces IL-10 Expression in CD4 T Cells

PLoS ONE ◽  
2014 ◽  
Vol 9 (3) ◽  
pp. e90855 ◽  
Author(s):  
Carmen Baca Jones ◽  
Christophe Filippi ◽  
Sowbarnika Sachithanantham ◽  
Teresa Rodriguez-Calvo ◽  
Katrin Ehrhardt ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cd4 T Cells ◽  
T Cell Proliferation ◽  
Chronic Viral Infection

Hepatocyte Growth Factor (HGF) Favors Monocyte Differentiation into Interleukin (IL)-10+IL-12neg Regulatory Dendritic Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2297-2297
Author(s):  
Sergio Rutella ◽  
Giuseppina Bonanno ◽  
Annabella Procoli ◽  
Andrea Mariotti ◽  
Nathalie Saulnier ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Cell Proliferation ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Growth Factor ◽  
Cd4 T Cells ◽  
T Cell Proliferation ◽  
Regulatory Dendritic Cells ◽  
Hepatocyte Growth

Abstract Dendritic cells (DCs) are highly specialized antigen presenting cells (APCs) with unique capacity to fully activate and induce clonal expansion of naive and memory T cells. Recently, DCs have been implicated in the maintenance of antigen (Ag)-specific unresponsiveness or tolerance through the induction of regulatory T (Treg) cells. Several hematopoietic growth factors, including interleukin-10 (IL-10), transforming growth factor-β1 (TGF-β1) and granulocyte colony-stimulating factor (G-CSF), might promote the differentiation of regulatory dendritic cells (DCs) in vivo and/or in vitro. Hepatocyte growth factor (HGF) is a pleiotropic cytokine and its effects on human DC differentiation and function have not been investigated. Monocytes cultured with HGF (HGF-DCs) differentiated into accessory cells with DC features, released low amounts of IL-12p70 and up-regulated IL-10 both at the mRNA and at the protein level. HGF-DCs displayed a CD14+CD1a−costimulationlow phenotype, and expressed the inhibitory receptor ILT3. Upon activation with HGF-DCs, allogeneic CD4+CD25− T cells up-regulated CD25 and the Treg-associated transcription factor FoxP3, proliferated poorly and released high levels of IL-10 but trace amounts of IL-2 and IFN-≤ . Interestingly, blockade of surface ILT3 on HGF-DCs or neutralization of secreted IL-10 translated into partial restoration of T-cell proliferation. Addition of exogenous IL-2 to CD4+ T cells initially primed with HGF-DCs was not associated with the enhancement of T cell proliferation. Secondary stimulation of HGF-DC-primed CD4+ T cells with immunogenic DCs differentiated with GM-CSF and IL-4 from monocytes of the same donor resulted in optimal T-cell proliferation. Interestingly, HGF-DC-primed CD4+ T cells significantly inhibited the proliferation of naive CD4+CD25− T cells in a cell contact-dependent manner, as shown by co-culture experiments with transwell inserts. Figure Figure Finally, DNA microarray analysis revealed a unique gene expression profile of HGF-activated monocytes. Specifically, HGF-DCs over-expressed a set of 217 genes implicated in cellular metabolism, signal transduction, cell adhesion, cell-to-cell signaling, inflammation and immune response. Genes up-regulated by HGF in freshly isolated monocytes are categorized according to their biological function Defense response 19 Cell adhesion and signaling 12 Signal transduction 32 Transcription regulation 17 Metabolism 35 Protein synthesis and degradation 24 Cytoskeletal organization 7 Transport 16 Chemotaxis 9 Cell proliferation and differentiation 6 Diverse physiological functions 9 Response to stress 9 Cell growth 4 Cell cycle 4 Morphogenesis 13 Unclassified 31 Of interest, HGF-DCs also upregulated mRNA signals for genes involved in tryptophan catabolisms, e.g., indoleamine 2,3-dioxygenase (IDO). Collectively, our findings point to a novel role for HGF in the regulation of monocyte/DC functions. From a therapeutic standpoint, HGF might represent an attractive target for immunotherapy.

scholarly journals Mapping of the autophagosomal degradome identifies IL-7Rα as key cargo in proliferating CD4+ T-cells

2021 ◽  
Author(s):  
Dingxi Zhou ◽  
Mariana Borsa ◽  
Daniel J. Puleston ◽  
Susanne Zellner ◽  
Jesusa Capera ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Surface Expression ◽  
T Cell Proliferation ◽  
Gamma Chain ◽  
Direct Identification ◽  
The Common ◽  
First Time

CD4+ T cells orchestrate both humoral and cytotoxic immune responses. While it is known that CD4+ T cell proliferation relies on autophagy, direct identification of the autophagosomal cargo involved is still missing. Here, we created a transgenic mouse model, which, for the first time, enables us to directly map the proteinaceous content of autophagosomes in any primary cell by LC3 proximity labelling. IL-7Rα, a cytokine receptor mostly found in naive and memory T cells, was reproducibly detected in autophagosomes of activated CD4+ T cells. Consistently, CD4+ T cells lacking autophagy showed increased IL-7Rα surface expression, while no defect in internalisation was observed. Mechanistically, excessive surface IL-7Rα sequestrates the common gamma chain, impairing the IL-2R assembly and downstream signalling crucial for T cell proliferation. This study provides proof-of-principle that key autophagy substrates can be reliably identified with this model to help mechanistically unravel autophagy's contribution to healthy physiology and disease.

scholarly journals TSLP and IL-7 use two different mechanisms to regulate human CD4+ T cell homeostasis

2009 ◽  
Vol 206 (10) ◽  
pp. 2111-2119 ◽  
Author(s):  
Ning Lu ◽  
Yi-Hong Wang ◽  
Yui-Hsi Wang ◽  
Kazuhiko Arima ◽  
Shino Hanabuchi ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd4 T Cell ◽  
Th2 Cells ◽  
T Cell Proliferation ◽  
T Cell Homeostasis ◽  
Cell Homeostasis ◽  
Th2 Differentiation

Whether thymic stromal lymphopoietin (TSLP) directly induces potent human CD4+ T cell proliferation and Th2 differentiation is unknown. We report that resting and activated CD4+ T cells expressed high levels of IL-7 receptor a chain but very low levels of TSLP receptor (TSLPR) when compared with levels expressed in myeloid dendritic cells (mDCs). This was confirmed by immunohistology and flow cytometry analyses showing that only a subset of mDCs, with more activated phenotypes, expressed TSLPR in human tonsils in vivo. IL-7 induced strong STAT1, -3, and -5 activation and promoted the proliferation of naive CD4+ T cells in the presence of anti-CD3 and anti-CD28 monoclonal antibodies, whereas TSLP induced weak STAT5 activation, associated with marginally improved cell survival and proliferation, but failed to induce cell expansion and Th2 differentiation. The effect of TSLP on enhancing strong human T cell proliferation was observed only when sorted naive CD4+ T cells were cultured with mDCs at levels as low as 0.5%. TSLP could only induce naive CD4+ T cells to differentiate into Th2 cells in the presence of allogeneic mDCs. These results demonstrate that IL-7 and TSLP use different mechanisms to regulate human CD4+ T cell homeostasis.

scholarly journals Allergen-Induced C5a/C5aR1 Axis Activation in Pulmonary CD11b+ cDCs Promotes Pulmonary Tolerance through Downregulation of CD40

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 300 ◽  
Author(s):  
Konstantina Antoniou ◽  
Fanny Ender ◽  
Tillman Vollbrandt ◽  
Yves Laumonnier ◽  
Franziska Rathmann ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
T Cell Proliferation ◽  
C5a Receptor ◽  
The Impact

Activation of the C5/C5a/C5a receptor 1 (C5aR1) axis during allergen sensitization protects from maladaptive T cell activation. To explore the underlying regulatory mechanisms, we analyzed the impact of C5aR1 activation on pulmonary CD11b+ conventional dendritic cells (cDCs) in the context of house-dust-mite (HDM) exposure. BALB/c mice were intratracheally immunized with an HDM/ovalbumin (OVA) mixture. After 24 h, we detected two CD11b+ cDC populations that could be distinguished on the basis of C5aR1 expression. C5aR1− but not C5aR1+ cDCs strongly induced T cell proliferation of OVA-reactive transgenic CD4+ T cells after re-exposure to antigen in vitro. C5aR1− cDCs expressed higher levels of MHC-II and CD40 than their C5aR1+ counterparts, which correlated directly with a higher frequency of interactions with cognate CD4+ T cells. Priming of OVA-specific T cells by C5aR1+ cDCs could be markedly increased by in vitro blockade of C5aR1 and this was associated with increased CD40 expression. Simultaneous blockade of C5aR1 and CD40L on C5aR1+ cDCs decreased T cell proliferation. Finally, pulsing with OVA-induced C5 production and its cleavage into C5a by both populations of CD11b+ cDCs. Thus, we propose a model in which allergen-induced autocrine C5a generation and subsequent C5aR1 activation in pulmonary CD11b+ cDCs promotes tolerance towards aeroallergens through downregulation of CD40.

scholarly journals Bystander memory CD8 T cell proliferation after anti-CD40/IL-2 treatment is independent of CD4 T cells

2013 ◽  
Vol 1 (S1) ◽  
Author(s):  
Steven K Grossenbacher ◽  
Arta M Monjazeb ◽  
Julia Tietze ◽  
Gail D Sckisel ◽  
Annie Mirsoian ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Cd4 T Cells ◽  
Cd8 T Cell ◽  
T Cell Proliferation ◽  
Memory Cd8 T Cell

scholarly journals Regulatory T Cells Target Chemokine Secretion by Dendritic Cells Independently of Their Capacity To Regulate T Cell Proliferation

2011 ◽  
Vol 186 (12) ◽  
pp. 6807-6814 ◽  
Author(s):  
Sara Morlacchi ◽  
Valentina Dal Secco ◽  
Cristiana Soldani ◽  
Nicolas Glaichenhaus ◽  
Antonella Viola ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Proliferation

Regulatory T Cells Expanded by Autologous Mature Human Dendritic Cells Expressing Indoleamine 2,3-Dioxygenase Are Potent Suppressors of T Cell Proliferation.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1553-1553
Author(s):  
Davi d J. Chung ◽  
Marco Rossi ◽  
Emanuela Romano ◽  
Jennifer Pressley ◽  
Christophe Antczak ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
De Novo ◽  
T Cell Proliferation ◽  
Indoleamine 2,3 Dioxygenase ◽  
Naturally Occurring ◽  
Dose Dependent

Abstract Best characterized as initiators of immunity, dendritic cells (DCs) also play an integral role in immune modulation. Immature DCs, for example, process self-antigens to induce and maintain tolerance. The immunoregulatory effects of DCs, however, are not limited to immature subtypes. Immunogenic mature DCs can also induce T regs to curb immune responses. We have found that human monocyte-derived DCs (moDCs) upregulate the immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) with maturation and expand functionally active, naturally occurring as well as inducible regulatory T cells (T regs) in an IDO-dependent manner. Priming of resting bulk T cells with autologous, IDO-expressing, mature moDCs in the absence of exogenous cytokines results in up to 10-fold expansion of CD4+CD25hiFoxp3+CD127neg T cells that mediate significant dose-dependent suppression of both allogeneic and autologous T cells stimulated de novo by DCs. The expansion of T regs by IDO-expressing moDCs involves cell-to-cell contact, CD80/CD86 ligation, and IL-2. Autologous priming in the presence of a competitive inhibitor of IDO, 1-methyl-tryptophan, diminishes T reg expansion. Candidate T regs were further characterized after cytofluorographic sorting primed bulk T cells into CD4+CD25hi, CD4+CD25int, and CD4+CD25neg subpopulations. Post-sort analysis showed that >60% of the CD4+CD25hi cells coexpressed Foxp3, which was not present in the CD4+CD25neg cells. CD4+CD25hi T regs exerted dose-dependent inhibition of DC-stimulated allogeneic T cell proliferation, with >90% inhibition at a suppressor to responder T cell ratio of 1:1 and ~50% inhibition at a ratio of 1:25. CD4+CD25int cells produced intermediate suppression depending on dose, and CD4+CD25neg cells were not inhibitory. CD4+CD25hi T regs mediated similar suppression of autologous T cell responses to stimulation de novo by DCs. CD4+CD25hi T regs also inhibited the generation of cytotoxic T lymphocytes (CTLs) specific for the Wilms’ tumor gene product (WT-1). The addition of CD4+CD25hi T regs to CTL-priming cultures resulted in a >80% decrease in specific target cell lysis of a WT-1-expressing cell line. Separate studies showed that T reg-mediated suppression is contact dependent and also requires TGF-beta, suggesting inhibition by naturally occurring and inducible T regs, respectively. Depletion of CD4+CD25hi T cells from bulk T cells by negative immunoselection with anti-CD25 magnetic beads at the outset of autologous priming significantly blunts T reg expansion, indicating a requirement for pre-existing T regs in the bulk T cell population. T reg expansion also occurs in priming cultures using cytofluorographically-sorted CD4+CD25neg T cells, indicating de novo generation of T regs from CD4+CD25neg precursors. In summary, our results demonstrate a mechanism by which mature, IDO-expressing, human moDCs expand autologous, naturally occurring as well as inducible T regs that functionally suppress the proliferation of both autologous and allogeneic T cells. Inhibition of this counter-regulatory pathway should result in more sustained benefit from active DC-based immunotherapy.

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