Abstract 593: Vascular Inflammation and Hypertension are Attenuated with T Cell Deletion of Serum and Glucocorticoid-regulated Kinase 1 (SGK1)

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Allison E Norlander ◽  
Mohamed A Saleh ◽  
Arvind Pandey ◽  
Hana A Itani ◽  
Jing Wu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Angiotensin Ii ◽  
Cd8 T Cells ◽  
Vascular Dysfunction ◽  
Vascular Inflammation ◽  
Mesenteric Arteries ◽  
Dependent Manner ◽  
Salt Treatment ◽  
Cell Deletion

We have previously shown that the T cell-derived pro-inflammatory cytokine, interleukin 17A (IL-17A), is upregulated by and promotes angiotensin II-induced hypertension and contributes to vascular dysfunction. It was recently demonstrated that an excess of 40 mM of sodium chloride in culture enhances IL-17A production from CD4+ T cells in a Serum and Glucocorticoid-Regulated Kinase 1 (SGK1) dependent manner. We confirmed the effect of salt on CD4+ T cell differentiation and extended this finding to CD8+ T cells in which 40mM of excess salt increased the expression of IL-17A (4.7 fold, p=0.0003) and the salt-sensing kinase SGK1 (2.2 fold, p=.001) in naive CD8+ T cells cultured under Th17 polarizing conditions. Since dietary salt intake is associated with hypertension, we hypothesized that T cell SGK1 promotes hypertension and contributes to vascular dysfunction. To test this hypothesis, we crossed SGK1 fl/fl mice with CD4cre mice to delete SGK1 in most T lymphocytes. Loss of T cell SGK1 resulted in a blunted blood pressure response to angiotensin II infusion (24.8 mmHg reduction, p=0.01) and DOCA-salt treatment (15.51 mmHg reduction, p<0.05). Moreover, vascular inflammation in response to angiotensin II infusion and/or DOCA-salt treatment was abrogated in these mice compared to SGK1 fl/fl control mice. Angiotensin II increased total (CD45+) leukocytes in the aorta from 5.7 to 52.4x10 3 (p<0.01) in SGK1 fl/fl mice compared to no increase in mice with T cell deletion of SGK1 (16.1 to 10.1x10 3 , p=ns). DOCA-salt induction increased total (CD45+) leukocytes in the aorta in SGK1 fl/fl mice from 7.4 to 20.6x10 3 (p<0.05) compared to no increase in mice with T cell deletion of SGK1 (8.7 to 10.8x10 3 , p=ns). Furthermore, preliminary data show that angiotensin II infusion impairs vascular relaxation in mesenteric arteries isolated from SGK1 fl/fl control mice, while this effect is blunted in angiotensin II treated mice with T cell deletion of SGK1. These studies demonstrate that T cell SGK1 may be a novel therapeutic target for hypertension and its associated vascular dysfunction.

Abstract 044: Deletion of Serum and Glucocorticoid-regulated Kinase 1 (SGK1) in T Cells Attenuates Hypertension and Renal/Vascular Dysfunction

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Allison E Norlander ◽  
Mohamed A Saleh ◽  
Arvind K Pandey ◽  
Hana A Itani ◽  
Jing Wu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Organ Dysfunction ◽  
Salt Intake ◽  
Blood Pressure Response ◽  
Vascular Dysfunction ◽  
Dependent Manner ◽  
Ang Ii ◽  
Dietary Salt ◽  
Cell Deletion

We have previously shown that the T cell-derived pro-inflammatory cytokine, interleukin 17A (IL17A), is upregulated by and promotes angiotensin II (Ang II)-induced hypertension and contributes to renal and vascular dysfunction. It was recently demonstrated that an excess of 40 mM of sodium chloride enhances IL17A production from CD4+ T cells in an SGK1 dependent manner. Since dietary salt intake is associated with hypertension, we hypothesized that T cell SGK1 promotes hypertension and contributes to end-organ dysfunction. To test this hypothesis, we crossed SGK1 fl/fl mice with Tg CD4cre mice to delete SGK1 in T lymphocytes. Loss of T cell SGK1 resulted in a blunted blood pressure response following 2 weeks of Ang II infusion (24.8 mmHg reduction, p=0.01). Moreover, renal and vascular inflammation in response to Ang II infusion was abrogated in these mice compared to SGK1 fl/fl control mice. Ang II infusion increased total (CD45+) leukocytes in the kidney from 55.4 to 120.4 x10 3 (p<0.01) in SGK1 fl/fl mice while there was no increase in mice with T cell deletion of SGK1 (48.1 to 47.5x10 3 , p=ns). Similarly, Ang II increased total (CD45+) leukocytes in the aorta from 5.7 to 52.4x10 3 (p<0.01) in SGK1 fl/fl mice compared to no increase in mice with T cell deletion of SGK1 (16.1 to 10.1x10 3 , p=ns). Furthermore, relaxation of mesenteric arterioles isolated from Ang II infused SGK1 fl/fl mice in response to acetylcholine was impaired by 22.37% (p<0.0001) compared to a 2.62% (p=ns) impairment in vessels isolated from mice with T cell deletion of SGK1, demonstrating that the latter group has preserved endothelial function despite Ang II infusion. To assess renal dysfunction, we measured urinary albumin:creatinine ratio which increased 5.81-fold (p<0.01) in SGK1 fl/fl mice infused with Ang II compared to 3.23-fold (p=ns) in mice without T cell SGK1, demonstrating that these mice are protected from Ang II-induced renal injury. Finally, we found that total numbers of splenic CD4+IL17A+ cells increase from 0.44% to 1.15% (p<0.05) in SGK1 fl/fl mice infused with Ang II compared to no change (0.45% to 0.47%, p=ns) in mice without T cell SGK1. These studies demonstrate that T cell SGK1 may be a novel therapeutic target for hypertension and the associated end-organ dysfunction.

scholarly journals Targeting CD38 is lethal to Breg-like chronic lymphocytic leukemia cells and Tregs, but restores CD8+ T-cell responses

2020 ◽  
Vol 4 (10) ◽  
pp. 2143-2157 ◽  
Author(s):  
Alak Manna ◽  
Timothy Kellett ◽  
Sonikpreet Aulakh ◽  
Laura J. Lewis-Tuffin ◽  
Navnita Dutta ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Xenograft Model ◽  
Lymphocytic Leukemia ◽  
Dependent Manner

Abstract Patients with chronic lymphocytic leukemia (CLL) are characterized by monoclonal expansion of CD5+CD23+CD27+CD19+κ/λ+ B lymphocytes and are clinically noted to have profound immune suppression. In these patients, it has been recently shown that a subset of B cells possesses regulatory functions and secretes high levels of interleukin 10 (IL-10). Our investigation identified that CLL cells with a CD19+CD24+CD38hi immunophenotype (B regulatory cell [Breg]–like CLL cells) produce high amounts of IL-10 and transforming growth factor β (TGF-β) and are capable of transforming naive T helper cells into CD4+CD25+FoxP3+ T regulatory cells (Tregs) in an IL-10/TGF-β-dependent manner. A strong correlation between the percentage of CD38+ CLL cells and Tregs was observed. CD38hi Tregs comprised more than 50% of Tregs in peripheral blood mononuclear cells (PBMCs) in patients with CLL. Anti-CD38 targeting agents resulted in lethality of both Breg-like CLL and Treg cells via apoptosis. Ex vivo, use of anti-CD38 monoclonal antibody (mAb) therapy was associated with a reduction in IL-10 and CLL patient-derived Tregs, but an increase in interferon-γ and proliferation of cytotoxic CD8+ T cells with an activated phenotype, which showed an improved ability to lyse patient-autologous CLL cells. Finally, effects of anti-CD38 mAb therapy were validated in a CLL–patient-derived xenograft model in vivo, which showed decreased percentage of Bregs, Tregs, and PD1+CD38hiCD8+ T cells, but increased Th17 and CD8+ T cells (vs vehicle). Altogether, our results demonstrate that targeting CD38 in CLL can modulate the tumor microenvironment; skewing T-cell populations from an immunosuppressive to immune-reactive milieu, thus promoting immune reconstitution for enhanced anti-CLL response.

scholarly journals The architectural design of CD8+ T cell responses in acute and chronic infection: Parallel structures with divergent fates

2021 ◽  
Vol 218 (4) ◽  
Author(s):  
H. Kay Chung ◽  
Bryan McDonald ◽  
Susan M. Kaech
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Architectural Design ◽  
Viral Infections ◽  
Population Heterogeneity ◽  
T Cell Subsets ◽  
Dependent Manner ◽  
Cell Immunity ◽  
And Migration

In response to infection, T cells adopt a range of differentiation states, creating numerous heterogeneous subsets that exhibit different phenotypes, functions, and migration patterns. This T cell heterogeneity is a universal feature of T cell immunity, needed to effectively control pathogens in a context-dependent manner and generate long-lived immunity to those pathogens. Here, we review new insights into differentiation state dynamics and population heterogeneity of CD8+ T cells in acute and chronic viral infections and cancer and highlight the parallels and distinctions between acute and chronic antigen stimulation settings. We focus on transcriptional and epigenetic networks that modulate the plasticity and terminal differentiation of antigen-specific CD8+ T cells and generate functionally diverse T cell subsets with different roles to combat infection and cancer.

scholarly journals Naïve CD8 T cell IFNγ responses to a vacuolar antigen are regulated by an inflammasome-independent NLRP3 pathway and Toxoplasma gondii ROP5

2020 ◽  
Author(s):  
Angel K. Kongsomboonvech ◽  
Felipe Rodriguez ◽  
Anh L. Diep ◽  
Brandon M. Justice ◽  
Brayan E. Castallanos ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Toxoplasma Gondii ◽  
Cd8 T Cells ◽  
Immune Cell ◽  
Cd8 T Cell ◽  
Inflammasome Activation ◽  
Phenotypic Variance ◽  
Dependent Manner ◽  
Presentation Pathway

ABSTRACTHost resistance to Toxoplasma gondii relies on CD8 T cell IFNγ responses, which if modulated by the host or parasite could influence chronic infection and parasite transmission between hosts. Since host-parasite interactions that govern this response are not fully elucidated, we investigated requirements for eliciting naïve CD8 T cell IFNγ responses to a vacuolar resident antigen of T. gondii, TGD057. Naïve TGD057 antigen-specific CD8 T cells (T57) were isolated from transnuclear mice and responded to parasite-infected bone marrow-derived macrophages (BMDMs) in an antigen-dependent manner, first by producing IL-2 and then IFNγ. T57 IFNγ responses to TGD057 were independent of the parasite’s protein export machinery ASP5 and MYR1. Instead, host immunity pathways downstream of the regulatory Immunity-Related GTPases (IRG), including partial dependence on Guanylate-Binding Proteins, are required. Multiple T. gondii ROP5 isoforms and allele types, including ‘avirulent’ ROP5A from clade A and D parasite strains, were able to suppress CD8 T cell IFNγ responses to parasite-infected BMDMs. Phenotypic variance between clades B, C, D, F, and A strains suggest T57 IFNγ differentiation occurs independently of parasite virulence or any known IRG-ROP5 interaction. Consistent with this, removal of ROP5 is not enough to elicit maximal CD8 T cell IFNγ production to parasite-infected cells. Instead, macrophage expression of the pathogen sensors, NLRP3 and to a large extent NLRP1, were absolute requirements. Other members of the conventional inflammasome cascade are only partially required, as revealed by decreased but not abrogated T57 IFNγ responses to parasite-infected ASC, caspase-1/11, and gasdermin D deficient cells. Moreover, IFNγ production was only partially reduced in the absence of IL-12, IL-18 or IL-1R signaling. In summary, T. gondii effectors and host machinery that modulate parasitophorous vacuolar membranes, as well as NLR-dependent but inflammasome-independent pathways, determine the full commitment of CD8 T cells IFNγ responses to a vacuolar antigen.AUTHOR SUMMARYParasites are excellent “students” of our immune system as they can deflect, antagonize and confuse the immune response making it difficult to vaccinate against these pathogens. In this report, we analyzed how a widespread parasite of mammals, Toxoplasma gondii, manipulates an immune cell needed for immunity to many intracellular pathogens, the CD8 T cell. Host pathways that govern CD8 T cell production of the immune protective cytokine, IFNγ, were also explored. We hypothesized the secreted Toxoplasma virulence factor, ROP5, work to inhibit the MHC 1 antigen presentation pathway therefore making it difficult for CD8 T cells to see T. gondii antigens sequestered inside a parasitophorous vacuole. However, manipulation through T. gondii ROP5 does not fully explain how CD8 T cells commit to making IFNγ in response to infection. Importantly, CD8 T cell IFNγ responses to T. gondii require the pathogen sensor NLRP3 to be expressed in the infected cell. Other proteins associated with NLRP3 activation, including members of the conventional inflammasome activation cascade pathway, are only partially involved. Our results identify a novel pathway by which NLRP3 regulates T cell function and underscore the need for inflammasome-activating adjuvants in vaccines aimed at inducing CD8 T cell IFNγ responses to parasites.

scholarly journals Eltrombopag: More Than Just a Thrombopoietin Receptor Agonist (TPO-RA) in Immune Thrombocytopenia (ITP)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2364-2364
Author(s):  
Anwar A. Sayed ◽  
Amna Malik ◽  
Grace Ayoola ◽  
Elisa Lucchini ◽  
Sasfia Candrianita ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Board Of Directors ◽  
Cd8 T Cells ◽  
Ex Vivo ◽  
Granzyme B ◽  
Immunomodulatory Effect ◽  
Dependent Manner ◽  
Advisory Committees ◽  
Dose Dependent

Immune thrombocytopenia (ITP) is an autoimmune disorder characterized by a skewed proinflammatory T cell profile. Thrombopoietin-receptor agonists (TPO-RA) have largely replaced immunosuppressants in the management of this disorder, with some patients achieving remission after a period of treatment with TPO-RA. The potential immune modulatory role of TPO-RA has not been fully investigated. The two current TPO-RA licensed for use in ITP; Eltrombopag (Elt) and Romiplostim (Romi) act on different parts of the TPO-R and have similar response rates. However, patients can respond to one agent but not the other. Elt has been described to have a strong iron chelating effect, and hence we propose that it may have an additive immunomodulatory effect on the T cells, absent in Romi. We determined the immunomodulatory effect of Elt by assessing the proliferation and functionality of T-cell lines and primary T-cells. T cell proliferation was assessed using both CFSE proliferation assay and MTT cell viability assay. T cell phenotype and functionality were assessed by multicolor surface and intracellular flow cytometric staining. Cells were co-cultured with Elt and Romi in vitro and ex vivo with both Jurkat and DG75 cells lines as well as primary cells, respectively. Deferoxamine (DFX) was used as a positive control for iron-chelation, and human TPO was used as a positive control for TPO-RA. All treatment doses were based on their calculated therapeutic serum levels. Mann Whitney U and Kruskal-Wallis H statistical tests were applied where applicable, and a P value of less than 0.05 were considered significant. Elt significantly decreased Jurkat T cells proliferation in a dose-dependent manner compared to no treatment and Romi. DFX, an iron chelator, also decreased Jurkat T cell proliferation to comparable levels of Elt. Interestingly, this anti-proliferative effect of Elt was only observed on Jurkat T cells, but not DG75 B cell line. Ex vivo CFSE proliferation assay was performed on primary CD4 and CD8 T cells assessing the antiproliferative effect of Elt. Elt significantly reduced proliferation compared to no treatment. DFX exhibited a similar antiproliferative effect on primary T cells, however, less potent compared to Elt. Neither Romi nor TPO affected the proliferation of Jurkat cells, DG75 cells or primary T cells. The functionality of CD4 and CD8 T cells was assessed based on the capacity of T cells to produce intracellular TNFα, IFNγ and Granzyme B. Elt significantly reduced the percentages of TNFα+/IFNγ+ CD4+ and CD8+ T cells in a dose-dependent manner. This reduction was also observed, albeit to a lesser extent, when T cells were treated with DFX. Furthermore, Granzyme B expression in CD8+ T cells was significantly reduced when cells were treated Elt, compared to no treatment. Romi did not affect the frequency of CD8+ TNFα+/IFNγ+ populations nor the expression of Granzyme B in CD8+ T cells. CD4+ and CD8+ T cells did not express TPO-R on their surface. To confirm the immunomodulatory role of Elt in vivo, the terminally-differentiated effector (CD45RA+CD62L-) CD8+ T cells were assessed in 13 Elt-treated patients and 11 Romi-treated patients. Patients on Elt had significantly reduced frequency of effector CD8 T cells compared to Romi-treated patients (44% vs 76.8%; p<0.01). Taken together, these novel findings suggest an off target immunomodulatory nature of Elt besides its thrombopoietic effect. This dose-dependent immunomodulatory effect is not TPO-R dependent and targets T cells primarily. This study is the first to display such property of Elt and could explain why there is a differential response to Elt and Romi. We hypothesise that Elt may be more effective in patients with T cell mediated disease, whilst patients with predominantly antibody mediated disease are more likely respond to Romi. These findings can also offer an explanation for Elt effectiveness in other T cell-mediated autoimmune conditions such as Aplastic Anemia. Disclosures Cooper: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Rigel: Consultancy, Membership on an entity's Board of Directors or advisory committees; Principia: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

IMMU-52. EFFECTS OF IMMUNE CHECKPOINT BLOCKADE ON ANTIGEN-SPECIFIC CD8+ T CELLS FOR USE IN ADOPTIVE CELLULAR THERAPY

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi104-vi104
Author(s):  
Elizabeth Ogando-Rivas ◽  
Paul Castillo ◽  
Noah Jones ◽  
Vrunda Trivedi ◽  
Jeffrey Drake ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cellular Therapy ◽  
Checkpoint Inhibitors ◽  
Cell Subset ◽  
Checkpoint Blockade ◽  
Immune Checkpoints ◽  
Effector Memory ◽  
Dependent Manner

Abstract BACKGROUND Adoptive T-cell therapies have been successfully used as treatment for patients diagnosed with advanced cancers. Unfortunately, for some refractory cancers, they have failed. To overcome this, checkpoint inhibitors have shown to rescue immune anti-tumor responses. We hypothesized that in-vitro checkpoint blockade during T-cell stimulation and expansion with RNA-pulsed dendritic cells may enhance the activity of antigen-specific T-cells and improve the efficacy of ACT platforms. METHODS Human PBMCs were isolated from CMV seropositive donors to generate DCs and pulsed them with CMVpp65-mRNA to educate T-cells in co-culture for 15-days. We targeted pp65 antigen which is ubiquitously expressed by glioblastoma cells. Three checkpoint blockade conditions were evaluated (anti-PD1, anti-Tim3 and anti-PD1+Tim3). IL2 was added every 3 days as well as the blockade antibodies. Immunephenotyping was performed on Day-0 and Day-15. Polyfunctional antigen specific responses were evaluated upon rechallenge with CMVpp65 peptides. RESULTS CMVpp65 activated CD8+ T-cells upregulate Lag3 and Tim3 (p= &lt; 0.0001). Tim3 blockade alone or in combination led to a significant upregulation of Lag3 expression on CD8+pp65Tetramer+ central memory, effector memory, and TEMRA T-cells. This latter T-cell subset uniquely maintain double-positive Tim3/Lag3 expression after blockade. In contrast, PD-1 blockade had minimal effects on Tim3 or Lag3 expression. In addition, IFN-g secretion was reduced in T-cells treated with Tim3 blockade in a dose-dependent manner (p= 0.004). CONCLUSION In this study, we have identified a potential activating component of Tim3 and linkage between Tim3 and Lag3 signaling upon blocking Tim3 axis during T-cell antigen presenting cell interactions that should be considered when targeting immune checkpoints for clinical use.

scholarly journals Prevention of CD8 T Cell Deletion during Chronic Viral Infection

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1189
Author(s):  
David G. Brooks ◽  
Antoinette Tishon ◽  
Michael B. A. Oldstone ◽  
Dorian B. McGavern
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Replication ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Chronic Viral Infection ◽  
Loss Of Function ◽  
Cell Deletion

During chronic viral infections, CD8 T cells rapidly lose antiviral and immune-stimulatory functions in a sustained program termed exhaustion. In addition to this loss of function, CD8 T cells with the highest affinity for viral antigen can be physically deleted. Consequently, treatments designed to restore function to exhausted cells and control chronic viral replication are limited from the onset by the decreased breadth of the antiviral T cell response. Yet, it remains unclear why certain populations of CD8 T cells are deleted while others are preserved in an exhausted state. We report that CD8 T cell deletion during chronic viral infection can be prevented by therapeutically lowering viral replication early after infection. The initial resistance to deletion enabled long-term maintenance of antiviral cytolytic activity of the otherwise deleted high-affinity CD8 T cells. In combination with decreased virus titers, CD4 T cell help and prolonged interactions with costimulatory molecules B7-1/B7-2 were required to prevent CD8 T cell deletion. Thus, therapeutic strategies to decrease early virus replication could enhance virus-specific CD8 T cell diversity and function during chronic infection.

scholarly journals TRAIL-expressing CD8+ T cells mediate tolerance following soluble peptide-induced peripheral T cell deletion

2010 ◽  
Vol 88 (6) ◽  
pp. 1217-1225 ◽  
Author(s):  
Prajwal Gurung ◽  
Tamara A. Kucaba ◽  
Stephen P. Schoenberger ◽  
Thomas A. Ferguson ◽  
Thomas S. Griffith
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Soluble Peptide ◽  
Cell Deletion

CD4+ and CD8+ anergic T cells induced by interleukin-10–treated human dendritic cells display antigen-specific suppressor activity

Blood ◽  
2002 ◽  
Vol 99 (7) ◽  
pp. 2468-2476 ◽  
Author(s):  
Kerstin Steinbrink ◽  
Edith Graulich ◽  
Sebastian Kubsch ◽  
Jürgen Knop ◽  
Alexander H. Enk
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Interleukin 10 ◽  
Cell Contact ◽  
Dependent Manner ◽  
Suppressor Activity ◽  
T Cell Clone ◽  
Anergic T Cells

Interleukin-10 (IL-10)–treated dendritic cells (DCs) induce an alloantigen- or peptide-specific anergy in various CD4+ and CD8+ T-cell populations. In the present study, we analyzed whether these anergic T cells are able to regulate antigen-specific immunity. Coculture experiments revealed that alloantigen-specific anergic CD4+ and CD8+ T cells suppressed proliferation of syngeneic T cells in a dose-dependent manner. The same effect was observed when the hemagglutinin-specific CD4+T-cell clone HA1.7 or tyrosinase-specific CD8+ T cells were cocultured with anergic T cells of the same specificity. Anergic T cells did not induce an antigen-independent bystander inhibition. Suppression was dependent on cell-to-cell contact between anergic and responder T cells, required activation by antigen-loaded DCs, and was not mediated by supernatants of anergic T cells. Furthermore, anergic T cells displayed an increased extracellular and intracellular expression of cytotoxic T-lymphocye antigen (CTLA)–4 molecules, and blocking of the CTLA-4 pathway restored the T-cell proliferation up to 70%, indicating an important role of the CTLA-4 molecule in the suppressor activity of anergic T cells. Taken together, our experiments demonstrate that anergic T cells induced by IL-10–treated DCs are able to suppress activation and function of T cells in an antigen-specific manner. Induction of anergic T cells might be exploited therapeutically for suppression of cellular immune responses in allergic or autoimmune diseases with identified (auto) antigens.

scholarly journals Chronic virus infection compromises memory bystander T cell function in an IL-6/STAT1-dependent manner

2019 ◽  
Vol 216 (3) ◽  
pp. 571-586 ◽  
Author(s):  
Isabel Barnstorf ◽  
Mariana Borsa ◽  
Nicolas Baumann ◽  
Katharina Pallmer ◽  
Alexander Yermanos ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Virus Infection ◽  
Cd8 T Cells ◽  
Viral Infections ◽  
Dependent Manner ◽  
Chronic Viral Infections ◽  
And Function ◽  
The Impact ◽  
Lcmv Infection

Chronic viral infections are widespread among humans, with ∼8–12 chronic viral infections per individual, and there is epidemiological proof that these impair heterologous immunity. We studied the impact of chronic LCMV infection on the phenotype and function of memory bystander CD8+ T cells. Active chronic LCMV infection had a profound effect on total numbers, phenotype, and function of memory bystander T cells in mice. The phenotypic changes included up-regulation of markers commonly associated with effector and exhausted cells and were induced by IL-6 in a STAT1-dependent manner in the context of chronic virus infection. Furthermore, bystander CD8 T cell functions were reduced with respect to their ability to produce inflammatory cytokines and to undergo secondary expansion upon cognate antigen challenge with major cell-extrinsic contributions responsible for the diminished memory potential of bystander CD8+ T cells. These findings open new perspectives for immunity and vaccination during chronic viral infections.

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