scholarly journals 643 Vasoactive intestinal peptide as a novel immune checkpoint molecule in activated T cells

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A672-A672
Author(s):  
Sruthi Ravindranathan ◽  
Tenzin Passang Fnu ◽  
Edmund Waller
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vasoactive Intestinal Peptide ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Activated T Cells

BackgroundOnly a fraction of cancer patients responds to current antibody-based immune checkpoint inhibitors.1 Our lab has identified vasoactive intestinal peptide-receptor (VIP-R) signaling as a targetable immune checkpoint pathway in cancer. VIP is a small neuropeptide with known immunosuppressive effects on T cells, in particular, CD4+ T cells.2–5 However, little is known about VIP-R signaling in CD8+ T cells. To define mechanisms by which VIP limits T cell activation and function, we studied the regulation of VIP and VIP receptors (VIP-R) in T cells following their activation in vitro and in mouse models of cancer.MethodsT cells from healthy human donors and murine splenocytes were activated using anti-CD3 coated plates. Western blots measured intracellular pre-pro-VIP, along with its cognate receptors; VPAC1 and VPAC2. Purified cultures of CD4+ and CD8+ T cells were used to interrogate the protein expression on specific T cell subsets. Activation and chemokine receptor expression was assessed by flow cytometry to evaluate T cell response to VIP-R antagonists in vitro and in tumor-bearing mice engrafted with pancreatic cancer cell lines.ResultsBoth murine and human T cells upregulate pre-pro-VIP following TCR stimulation with similar kinetics of VIP receptors between species. VIP expression is upregulated in vivo following treatment of tumor-bearing mice with anti-PD1 MoAb. VIP expression is temporally correlated with the upregulation of other co-inhibitory molecules. VPAC1 expression modestly increased in activated T cells while VPAC2 expression decreased. A non-canonical high molecular weight (HMW) form of VPAC2-related protein robustly and transiently increase in activated T cells. Expression of HMW form of VPAC2 is only detected in activated CD4+ T cells. Of note, activated CD4+ but not CD8+ T cells upregulate pre-pro-VIP. Pharmacological inhibition of VIP-R signaling significantly increased CD69+, OX40+, Lag3+, and PD1+ expression in CD4+ subsets compared to activated T cells without VIP-R antagonists (p < 0.05). In contrast, CD8+ T cells upregulate VPAC1 but not VPAC2 receptor following activation. VIP-R antagonist treatment of activated CD8+ T cells significantly decreased CXCR4+ expression (p < 0.05). CXCR3 and CXCR5 expression were not affected by VIP-R antagonist treatment.ConclusionsVIP-R signaling is a novel immune autocrine and paracrine checkpoint pathway in activated CD4+ T cells. Activated CD4+ and CD8+ T cells demonstrate different kinetics of VPAC1 and VPAC2 expression, suggesting different immune-regulatory responses to VIP-R antagonists. Understanding VIP-R signaling induced during T cell activation can lead to specific drugs that target VIP-R pathways to enhance cancer immunotherapy.AcknowledgementsWe thank healthy volunteers for blood samples. The authors also thank the shared resources at Emory University, namely, Emory Flow Cytometry Core (EFCC) and Integrated Cellular Imaging Core (ICI) and Yerkes Nonhuman Primate Genomics Core that provided services or instruments at subsidized cost to conduct some of the reported experiments. This work was supported in part by Katz Foundation funding, Georgia Research Alliance, and Emory School of Medicine Dean's Imagine, Innovate and Impact (I3) venture award to Edmund K. Waller.ReferencesDarvin P, Toor SM, Sasidharan Nair V, Elkord E. Immune checkpoint inhibitors: recent progress and potential biomarkers. Experimental and Molecular Medicine 2018.Wang HY, Jiang XM, Ganea D. The Neuropeptides VIP and PACAP Inhibit IL-2 Transcription by Decreasing c-Jun and Increasing JunB Expression in T Cells. J Neuroimmunol 2000;104(1):68–78.Delgado M. Vasoactive intestinal peptide generates CD4+CD25+ regulatory T Cells in Vivo. J Leukoc Biol 2005.Anderson P, Gonzalez-Rey E. Vasoactive intestinal peptide induces cell cycle arrest and regulatory functions in human T cells at multiple levels. Mol Cell Biol 2010.Delgado M, Ganea D. Vasoactive intestinal peptide: a neuropeptide with pleiotropic immune functions. Amino Acids. NIH Public Access July 2013, 25–39.Ethics ApprovalDe-identified blood samples from consented healthy volunteers (IRB 00046063) were obtained with approval from Institutional Review Boards.

scholarly journals 781 Validation of the combinatorial effect of blinatumomab and nivolumab in cancer therapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A831-A831
Author(s):  
Tienan Wang ◽  
Qing Lin ◽  
Jie Zhang
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Culture System ◽  
Cell Activation ◽  
Checkpoint Inhibitors

BackgroundCancer immunotherapies, including immune checkpoint inhibitors, CAR-T, cancer vaccines and bispecific antibodies, have been brought to spot light in recent years as several therapeutic strategies targeting the immune system have produced exciting clinical results. Bispecific antibody typically play dual roles in blocking the immune checkpoint and redirecting/re-boosting the function of the immune effector cells. Blinatumomab belongs to CD3 bispecific T cell engager (CD3 BiTE), which was engineered to harbor two arms binding with CD3 and CD19 simultaneously and direct CD8+ T cells to specifically recognize CD19 positive lymphoma cells to execute cytotoxicity. Approval of Blinatumomab for patients with relapse/refractory B cell acute lymphoblastic leukemia (ALL) has driven remarkable increase in combination studies of Blinatumomab with other immunotherapies such as checkpoint inhibitors.MethodsIn this study, we developed CD8+ T cytotoxic system targeting different B lymphoma cell line and fully validated the function of Blinatumomab in promoting target tumor cell lysis by primary CD8+ T cells (figure 1). In addition, we established a mixed lymphocyte and tumor system to mimic physiological TME to dissect the combinational role of Nivolumab and Blinatumomab (figure 2).ResultsThe result suggest that combinatory therapy is highly depend on the dosage of Blinatumomab and also T cell number in the TME, which might give an instruction for ongoing clinical trial design. Finally, we have employed humanized mouse models bearing Raji or Daudi tumor cells to further validate this combination treatment in vivo. Both In-vivo and In-vitro data support that Blinatumomab is dominant in activing T cell and Nivolumab can only exhibit synergistic effect under suboptimal dosage of Blinatumomab.Abstract 781 Figure 1Establishment of In vitro co-culture system for CD3 BiTEestablish in vitro human PBMC based system to validate CD3 BiTE functionAbstract 781 Figure 2Opdivo and CD3 BiTE CombinationOpdivo could further promote T cell activation under the treatment of CD3 BiTEConclusionsSuccessfully establish in vitro system to evaluate the function of CD3 BiTE and also take advantage of MLR/tumor co-culture system to demonstrate PD1 antibody could further promote T cell activation under appropriate dosage of CD3 BiTE.

scholarly journals Critical role for perforin and Fas-dependent killing of dendritic cells in the control of inflammation

Blood ◽  
2012 ◽  
Vol 119 (1) ◽  
pp. 127-136 ◽  
Author(s):  
Min Chen ◽  
Kumar Felix ◽  
Jin Wang
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Cell Types ◽  
Activated T Cells ◽  
Ifn Γ

AbstractAfter stimulation of antigen-specific T cells, dendritic cell (DCs) are susceptible to killing by these activated T cells that involve perforin and Fas-dependent mechanisms. Fas-dependent DC apoptosis has been shown to limit DC accumulation and prevent the development of autoimmunity. However, a role for perforin in the maintenance of DC homeostasis for immune regulation remains to be determined. Here we show that perforin deficiency in mice, together with the deletion of Fas in DCs (perforin−/−DC-Fas−/−), led to DC accumulation, uncontrolled T-cell activation, and IFN-γ production by CD8+ T cells, resulting in the development of lethal hemophagocytic lymphohistiocytosis. Consistently, adoptive transfer of Fas−/− DCs induced over-activation and IFN-γ production in perforin−/− CD8+ T cells. Neutralization of IFN-γ prevented the spreading of inflammatory responses to different cell types and protected the survival of perforin−/−DC-Fas−/− mice. Our data suggest that perforin and Fas synergize in the maintenance of DC homeostasis to limit T cell activation, and prevent the initiation of an inflammatory cascade.

scholarly journals c-Jun NH2-Terminal Kinase (JNK)1 and JNK2 Have Distinct Roles in CD8+ T Cell Activation

2002 ◽  
Vol 195 (7) ◽  
pp. 811-823 ◽  
Author(s):  
Dietrich Conze ◽  
Troy Krahl ◽  
Norman Kennedy ◽  
Linda Weiss ◽  
Joanne Lumsden ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cd8 T Cell ◽  
Cell Surface Expression ◽  
Chain Gene ◽  
Α Chain

The c-Jun NH2-terminal kinase (JNK) signaling pathway is induced by cytokines and stress stimuli and is implicated in cell death and differentiation, but the specific function of this pathway depends on the cell type. Here we examined the role of JNK1 and JNK2 in CD8+ T cells. Unlike CD4+ T cells, the absence of JNK2 causes increased interleukin (IL)-2 production and proliferation of CD8+ T cells. In contrast, JNK1-deficient CD8+ T cells are unable to undergo antigen-stimulated expansion in vitro, even in the presence of exogenous IL-2. The hypoproliferation of these cells is associated with impaired IL-2 receptor α chain (CD25) gene and cell surface expression. The reduced level of nuclear activating protein 1 (AP-1) complexes in activated JNK1-deficient CD8+ T cells can account for the impaired IL-2 receptor α chain gene expression. Thus, JNK1 and JNK2 play different roles during CD8+ T cell activation and these roles differ from those in CD4+ T cells.

scholarly journals Quantitative Proteomics Reveals Protein Dysregulation During T Cell Activation in Multiple Sclerosis Patients Compared to Healthy Controls

2021 ◽  
Author(s):  
Chiara Cappelletti ◽  
Anna Maria Eriksson ◽  
Ina Skaara Brorson ◽  
Ingvild S. Leikfoss ◽  
Oda Glomstad Kråbøl ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Susceptibility Genes ◽  
Healthy Controls ◽  
Activated T Cells ◽  
Multiple Sclerosis Patients

Abstract Background: Multiple sclerosis (MS) is an autoimmune, neurodegenerative disorder with a strong genetic component that acts in a complex interaction with environmental factors for disease development. CD4 + T cells are pivotal players in MS pathogenesis, where peripherally activated T cells migrate to the central nervous system leading to demyelination and axonal degeneration. Through a proteomic approach, we aim at identifying dysregulated pathways in activated T cells from MS patients as compared to healthy controls. Methods: CD4 + T cells were purified from peripheral blood from MS patients and healthy controls by magnetic separation. Cells were left unstimulated or stimulated in vitro through the TCR and costimulatory CD28 receptor for 24 hours prior to sampling. Electrospray liquid chromatographytandem mass spectrometry was used to measure protein abundances. Results: Upon T cell activation the abundance of 1,801 proteins was changed. Among these proteins, we observed an enrichment of proteins expressed by MS-susceptibility genes. When comparing protein abundances in T cell samples from healthy controls and MS patients, 18 and 33 proteins were differentially expressed in unstimulated and stimulated CD4 + T cells, respectively. Moreover, 353 and 304 proteins were identified as proteins exclusively induced upon T cell activation in healthy controls and MS patients, respectively and dysregulation of the Nur77 pathway was observed only in samples from MS patients. Conclusions: Our study highlights the importance of CD4 + T cell activation for MS, as proteins that change in abundance upon T cell activation are enriched for proteins encoded by MS susceptibility genes. The results provide evidence for proteomic disturbances in T cell activation in MS, and pinpoint to dysregulation of the Nur77 pathway, a biological pathway known to limit aberrant effector T cell responses.

Hepatic AAV Gene Transfer of Cytoplasmic Transgene Induces Transgene Product-Specific T Cell Activation Initially in the Liver and Celiac Lymph Node Preceding Treg Induction

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3241-3241
Author(s):  
Roland W. Herzog ◽  
George Q. Perrin
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Gene Transfer ◽  
Antigen Presentation ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Lymphoid Organs ◽  
Activated T Cells

Abstract In several published studies, we have shown induction of immune tolerance to coagulations factors by hepatic gene transfer to animals with hemophilia. Tolerance induction is influenced by a number of complex factors, most notably T cell activation and induction of antigen-specific CD4+CD25+FoxP3+ regulatory T cells (Treg). We sought to better understand antigen presentation to CD4+ T cells and the dynamics of the resulting T cell response. To characterize the interaction of adeno-associated virus (AAV) antigen expression in the liver with immune cells, we used an AAV8 vector, which have a high tropism for murine liver, expressing cytoplasmic ovalbumin (AAV8-Cyto-Ova) from the EF1α promoter. Use of AAV8-Cyto-Ova allowed us to eliminate effects from systemic antigen delivery. Vector was injected into the tail vein of DO11.10-transgenic RAG-/- mice, which contain exclusively Ova-specific CD4+ T cells and lack Treg. AAV8-Cyto-Ova caused upregulation of the very early activation marker CD69 on the CD4+ T cells as early as 2 weeks after gene transfer, with induced Treg emerging at about 3 weeks. CD69+CD4+ T cells were first observed in greatest numbers in the liver and celiac lymph node (LN), one of the liver-draining LN. This T cell activation persisted for several weeks. To better define the sites of T cell activation, we used the compound FTY720, which is an agonist of sphingosine-1-phosphate receptors and prevents migration of lymphocytes but does not alter T cell function. Two weeks after AAV8-Cyto-Ova, FTY720 sequestered activated T cells mostly in the liver and celiac LN, when compared to other lymphoid organs, indicating that these are the initial sites of T cell activation. At the 3-week time point, there were fewer activated T cells in the liver and celiac LN in mice that received FTY720, while instead accumulating in the blood. Most likely, activated T cells were prevented from reentering the lymphoid organs from the circulation, where they were sequestered. We conclude that T cells are first activated by AAV8-Cyto-Ova in the liver and celiac LN after two weeks, where they subsequently egress into the circulation and re-enter lymphoid tissues, with many returning to the liver and celiac LN. FTY720 given at 2 weeks prevented the newly activated T cells from leaving the liver and celiac LN. These results strongly suggest that antigen presentation and CD4+ T cell activation occur first in the liver and celiac LN, beginning about 2 weeks after vector administration. Consistent with this conclusion, adoptively transferred Ova-specific CD4+ T cells proliferated first and to a much greater degree in the celiac LN of AAV8-Cyto-Ova transduced mice. Inactiviating Kupffer cells with gadolinium chloride significantly reduced antigen-specific proliferation, illustrating the requirement for professional resident liver antigen-presenting cells. Furthermore, we show that - in contrast to the AAV expression of secreted Ova - Treg are exclusively extrathymically induced after AAV8-Cyto-Ova vector administration. These Treg are found in high numbers in the blood after 2 weeks in mice given the FTY720 compound, suggesting that these peripherally induced Treg quickly enter the circulation. In conclusion, the liver and its draining celiac LN are key sites for antigen presentation and T cell activation in response to transgene expression directed by hepatic gene transfer. Presentation of antigen derived from a non-secreted transgene product induces FoxP3+ Treg that rapidly distribute through the circulation. Disclosures Herzog: Novo Nordisk: Research Funding; Spark Therapeutics: Patents & Royalties: Patent licenses.

scholarly journals CTLA-4 dysregulation of self/tumor-reactive CD8+ T-cell function is CD4+ T-cell dependent

Blood ◽  
2006 ◽  
Vol 108 (12) ◽  
pp. 3818-3823 ◽  
Author(s):  
Luca Gattinoni ◽  
Anju Ranganathan ◽  
Deborah R. Surman ◽  
Douglas C. Palmer ◽  
Paul A. Antony ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Cell Function ◽  
Cd8 T Cell ◽  
Peripheral Tolerance ◽  
The Impact

AbstractCytotoxic T lymphocyte–associated antigen 4 (CTLA-4) maintains peripheral tolerance by suppressing T-cell activation and proliferation but its precise role in vivo remains unclear. We sought to elucidate the impact of CTLA-4 expression on self/tumor-reactive CD8+ T cells by using the glycoprotein (gp) 100–specific T-cell receptor (TCR) transgenic mouse, pmel-1. pmel-1 CLTA-4–/– mice developed profound, accelerated autoimmune vitiligo. This enhanced autoimmunity was associated with a small but highly activated CD8+ T-cell population and large numbers of CD4+ T cells not expressing the transgenic TCR. Adoptive transfer of pmel-1 CLTA-4–/– CD8+ T cells did not mediate superior antitumor immunity in the settings of either large established tumors or tumor challenge, suggesting that the mere absence of CTLA-4–mediated inhibition on CD8+ T cells did not directly promote enhancement of their effector functions. Removal of CD4+ T cells by crossing the pmel-1 CLTA-4–/– mouse onto a Rag-1–/– background resulted in the complete abrogation of CD8+ T-cell activation and autoimmune manifestations. The effects of CD4+ CLTA-4–/– T cells were dependent on the absence of CTLA-4 on CD8+ T cells. These results indicated that CD8+ CLTA-4–/– T-cell–mediated autoimmunity and tumor immunity required CD4+ T cells in which the function was dysregulated by the absence of CTLA-4–mediated negative costimulation.

Azacitidine Induces A Shift In Th1/Th17 Ratio and FoxP3 Expression In Anti-CD3 Stimulated CD4+ T-Cells; Implications for the Treatment of Myelodysplastic Syndromes

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4026-4026
Author(s):  
Hetty J Bontkes ◽  
Jurjen M Ruben ◽  
Theresia M. Westers ◽  
Gert J. Ossenkoppele ◽  
Arjan A. Van de Loosdrecht
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Th17 Cells ◽  
Dna Methyltransferase ◽  
Cell Activation ◽  
Foxp3 Expression ◽  
Cd4 T Cell ◽  
Activated T Cells

Abstract Abstract 4026 Aberrant DNA methylation and other epigenetic changes play a role in the development of myelodysplastic syndromes (MDS). Epigenetic drugs such as DNA methyltransferase inhibitors are therefore increasingly employed in MDS treatment regimens. Recent studies show that gene methylation processes also regulate T-cell function. Here we analyzed the in vitro effects of the DNA methyltransferase inhibitor ‘5-azacitidine (Aza) on CD4+ T-cell activation. We confirmed the previously described inhibition of proliferation and increased expression of FoxP3, the regulatory T-cell (Treg) marker, by anti-CD3 stimulated T-cells in the presence of 1mM Aza. Here we have sorted CD4+ T-cells isolated form healthy donor peripheral blood into CD25neg resting, CD25dim recently activated and CD25hi Treg cells. Aza facilitated the induction of CD25hiFoxP3+ T-cells from CD25neg (4.7% of vehicle treated cells versus 17.3% of Aza treated cells p=0.0007, n=9) and to a lesser extend from CD25dim (1.2% versus 8.6%, p=0.0015, n=7) CD4+ T-cells, while Aza had no effect on FoxP3 expression in CD25hi sorted cells, FoxP3 expression remained high. In addition, cytokine producing T-cells were enumerated after stimulation with phorbol-12-myristate-13-acetate (PMA) and ionomycin in the presence of Brefeldin A. Aza treatment increased the number of IFNγ producing cells in the total CD4+ population (19.1% versus 40.8%; p<0.0001, n=10) as well as among the CD25neg (5.7% vs 41.2%; p=0.001, n=8) and CD25dim CD4+ T-cell populations (28.4% versus 46.6%; p=0.06, n=7). TNFα producing cells were increased in the total CD4+ (36.4% versus 51.1%; p=0.011, n=9) and CD4posCD25dim (36.7% versus 52.3%; p=0.033, n=6) populations but not in the CD4posCD25neg cells (50.9% versus 51.1%; p=0.9, n=7). This increase in pro-inflammatory cytokine production indicates that Aza induces T-cell activation and that the increase in FoxP3 expression may reflect T-cell activation rather than an increase in bona fide Treg by Aza treatment. Indeed a proportion of the FoxP3+ cells was positive for TNFa or IFNg, suggesting that these are activated T-cells rather than Treg. However, the proportion of FoxP3+IFNγ- and FoxP3+TNFα- cells was significantly higher among Aza treated CD4+ cells (p=0.0037 and 0.0018 respectively, n=5), suggesting an increase in Treg as well. Functional assays to demonstrate that these FoxP3+ cells are indeed regulatory T-cells are currently being set up. Next to IFNγ and TNFα producing Th1 cells, the more recently described IL-17 committed Th17 cells have been described to play a role in low risk MDS. Furthermore, it has been shown that Treg can differentiate into IL-17 producing cells. We, therefore evaluated the effect of Aza on Th17 cells. Interestingly, in contrast to IFNγ and TNFα producing cells, the proportion of IL-17+IFNγ- Th17 cells among the total CD4+ population was reduced by Aza treatment (1.8% versus 1.1% p=0.035, n=10), leading to a significant increase in the Th1/Th17 ratio (14.0 versus 47.9, p=0.0005, n=10). In contrast, although the numbers were small, the proportion of Th17 cells was increased by Aza in the CD25neg population (0.08% versus 0.20%, p=0.028, n=8), suggesting that Aza may have differential effects on resting and recently activated T-cells. In conclusion, our data show that Aza increases the induction of FoxP3+ Treg and Th1 cells but inhibits IL-17 production, particularly by previously activated T-cells. Aza may therefore particularly be beneficial in pathogenic immune disorders characterized by increased Th17 numbers accompanied by reduced Treg frequencies, such as low-risk MDS. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Association of HLA Genotype With T-Cell Activation in Human Immunodeficiency Virus (HIV) and HIV/Hepatitis C Virus–Coinfected Women

2019 ◽  
Vol 221 (7) ◽  
pp. 1156-1166
Author(s):  
Andrea A Z Kovacs ◽  
Naoko Kono ◽  
Chia-Hao Wang ◽  
Daidong Wang ◽  
Toni Frederick ◽  
...  
Keyword(s):  
T Cells ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Immunodeficiency Virus ◽  
The Relationship

Abstract Background Global immune activation and HLA alleles are each associated with the pathogenesis of human immunodeficiency virus (HIV) and hepatitis C virus . Methods We evaluated the relationship between 44 HLA class I and 28 class II alleles and percentages of activated CD8 (CD8+CD38+DR+) and CD4 (CD4+CD38+DR+) T cells in 586 women who were naive to highly active antiretroviral therapy. We used linear generalized estimating equation regression models, adjusting for race/ethnicity, age, HIV load, and hepatitis C virus infection and controlling for multiplicity using a false discovery rate threshold of 0.10. Results Ten HLA alleles were associated with CD8 and/or CD4 T-cell activation. Lower percentages of activated CD8 and/or CD4 T cells were associated with protective alleles B*57:03 (CD8 T cells, −6.6% [P = .002]; CD4 T cells, −2.7% [P = .007]), C*18:01 (CD8 T cells, −6.6%; P &lt; .0008) and DRB1*13:01 (CD4 T cells, −2.7%; P &lt; .0004), and higher percentages were found with B*18:01 (CD8 T cells, 6.2%; P &lt; .0003), a detrimental allele. Other alleles/allele groups associated with activation included C*12:03, group DQA1*01:00, DQB1*03:01, DQB1*03:02, DQB1*06:02, and DQB1*06:03. Conclusion These findings suggest that a person’s HLA type may play a role in modulating T-cell activation independent of viral load and sheds light on the relationship between HLA, T-cell activation, immune control, and HIV pathogenesis.

scholarly journals The rationale behind targeting the ICOS-ICOS ligand costimulatory pathway in cancer immunotherapy

ESMO Open ◽  
2020 ◽  
Vol 5 (1) ◽  
pp. e000544 ◽  
Author(s):  
Cinzia Solinas ◽  
Chunyan Gu-Trantien ◽  
Karen Willard-Gallo
Keyword(s):  
T Cells ◽  
Cell Death ◽  
T Cell ◽  
Programmed Cell Death ◽  
T Cell Activation ◽  
Immune Checkpoint ◽  
Cell Activation ◽  
Cytotoxic T Lymphocyte ◽  
Immune Checkpoint Blockade ◽  
Activated T Cells

Inducible T cell costimulator (ICOS, cluster of differentiation (CD278)) is an activating costimulatory immune checkpoint expressed on activated T cells. Its ligand, ICOSL is expressed on antigen-presenting cells and somatic cells, including tumour cells in the tumour microenvironment. ICOS and ICOSL expression is linked to the release of soluble factors (cytokines), induced by activation of the immune response. ICOS and ICOSL binding generates various activities among the diversity of T cell subpopulations, including T cell activation and effector functions and when sustained also suppressive activities mediated by regulatory T cells. This dual role in both antitumour and protumour activities makes targeting the ICOS/ICOSL pathway attractive for enhancement of antitumour immune responses. This review summarises the biological background and rationale for targeting ICOS/ICOSL in cancer together with an overview of the principal ongoing clinical trials that are testing it in combination with anti-cytotoxic T lymphocyte antigen-4 and anti-programmed cell death-1 or anti-programmed cell death ligand-1 based immune checkpoint blockade.

scholarly journals Gamma Interferon Responses of CD4 and CD8 T-Cell Subsets Are Quantitatively Different and Independent of Each Other during Pulmonary Mycobacterium bovis BCG Infection

2007 ◽  
Vol 75 (5) ◽  
pp. 2244-2252 ◽  
Author(s):  
Patricia Ngai ◽  
Sarah McCormick ◽  
Cherrie Small ◽  
Xizhong Zhang ◽  
Anna Zganiacz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Mycobacterial Infection ◽  
Cd8 T Cell ◽  
T Cell Subsets ◽  
Ifn Γ

ABSTRACT Gamma interferon (IFN-γ) is a key cytokine in host defense against intracellular mycobacterial infection. It has been believed that both CD4 and CD8 T cells are the primary sources of IFN-γ. However, the relative contributions of CD4 and CD8 T-cell subsets to IFN-γ production and the relationship between CD4 and CD8 T-cell activation have not been examined. By using a model of pulmonary mycobacterial infection and various immunodetection assays, we found that CD4 T cells mounted a much stronger IFN-γ response than CD8 T cells at various times after mycobacterial infection, and this pronounced IFN-γ production by CD4 T cells was attributed to both greater numbers of antigen-specific CD4 T cells and a greater IFN-γ secretion capacity of these cells. By using major histocompatibility complex class II-deficient or CD4-deficient mice, we found that the lack of CD4 T cells did not negatively affect primary or secondary CD8 T-cell IFN-γ responses. The CD8 T cells activated in the absence of CD4 T cells were capable of immune protection against secondary mycobacterial challenge. Our results suggest that, whereas both CD4 and CD8 T cells are capable of IFN-γ production, the former represent a much greater cellular source of IFN-γ. Moreover, during mycobacterial infection, CD8 T-cell IFN-γ responses and activation are independent of CD4 T-cell activation.

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