scholarly journals 621 NKG2A and HLA-E define a novel mechanism of resistance to immunotherapy with M. bovis BCG in non-muscle-invasive bladder cancer patients

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A651-A651
Author(s):  
Amir Horowitz ◽  
Jorge Daza ◽  
Y Alice Wang ◽  
Daniel Ranti ◽  
Berengere Salome ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Autologous Tumor ◽  
T Cell Exhaustion ◽  
Bladder Tumors ◽  
Cell Exhaustion

Background75% of diagnosed bladder tumors are non-muscle-invasive (NMIBC)[1, 2]. Most require intravesical instillation of M.bovis Bacillus Calmette-Guérin (BCG). Recurrence after immunotherapy occurs in ~50% patients. Development of treatments for BCG-resistant disease has lagged partly because few studies have attempted to understand the relationship between timing of tumor recurrence, reasoning for the recurrence, and the state of immune system at the time of recurrence.Immune exhaustion is observed following microbial infections, cancers and chronic inflammation [3–5]. Natural Killer (NK) cells are among the earliest responders[6–8] and undergo a similar program of exhaustion as T cells[9]. HLA-E strongly inhibits NKG2A-expressing NK and CD8+T cells and is commonly upregulated on tumors[10]. We evaluated the potential restorative capacity of NKG2A and PD-L1-blockade for reinvigorating NK and CD8+T cell antitumor functions in in BCG-resistant bladder cancer.Methods mRNA analysis of 2,892 genes was performed on tumor tissue of NMIBC patients before and after BCG therapy (n=35). Immunostaining (serial-IHC,immunofluorescence,imaging-mass cytometry) was performed on consecutive tissue sections. Single-cell-RNA-sequencing (scRNAseq) was performed on fresh bladder tumors (NMIBC,n=4; MIBC,n=9). OLink Proteomics (”Inflammation” panel) was performed longitudinally on plasma/urine from a prospective cohort of NMIBC patients. Patient tumors (n=3) were expanded as organoids and co-cultured with autologous tumor-derived NK and CD8+T cells in presence/absence of anti-PD-L1/NKG2A antibodies.ResultsWe demonstrate a robust local TME and systemic response to BCG that correlates with chronic inflammation and adaptive resistance rather than with preventing tumor recurrence. This resistance is mediated through IFN-γ-production by tumor-infiltrating NKG2A+NK and NKG2A+PD-1+CD8+T cells and results in increased HLA-E and PD-L1 on recurring tumors. Co-culture of treatment-naïve NMIBC tumors with recombinant IFN-gamma directly enhanced expression of PD-L1 and HLA-E. Longitudinal analysis of plasma before and during BCG immunotherapy revealed an inflammatory signature, including but not limited to IFN-gamma, that is maintained throughout treatment.Immunostaining and scRNAseq of NMIBC specimens revealed highly enriched infiltration by NKG2A+NK and NKG2A+CD8+T cells in HLA-EBrightPD-L1+ tumors and were spatially organized relative to tumors in a manner suggesting direct inhibition. Tumor-derived NK and CD8+T cells from BCG-resistant patients were co-cultured with autologous tumor organoids. Preliminary analyses demonstrated an improved anti-tumor response in presence of NKG2A/PD-L1-blockade.ConclusionsOur data support a model of BCG-resistance that points to a novel checkpoint axis that contributes to BCG-resistance: HLA-E/NKG2A. New insights into this axis in NMIBC and how it is altered with repeated BCG exposure will enable us to explore combination therapies (PD-L1/NKG2A-blockade) that may reduce BCG-resistance and provide durable response.ReferencesEidinger D, Morales A: Discussion paper: treatment of superficial bladder cancer in man. Ann N Y Acad Sci 1976, 277:239–240.Morales A, Eidinger D, Bruce AW: Intracavitary Bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol 1976, 116:180–183.Blank CU, Haining WN, Held W, Hogan PG, Kallies A, Lugli E, Lynn RC, Philip M, Rao A, Restifo NP et al: Defining ‘T cell exhaustion’. Nat Rev Immunol 2019, 19:665–674.Hashimoto M, Kamphorst AO, Im SJ, Kissick HT, Pillai RN, Ramalingam SS, Araki K, Ahmed R: CD8 T Cell Exhaustion in Chronic Infection and Cancer: Opportunities for Interventions. Annu Rev Med 2018, 69:301–318.McLane LM, Abdel-Hakeem MS, Wherry EJ: CD8 T Cell Exhaustion During Chronic Viral Infection and Cancer. Annu Rev Immunol 2019, 37:457–495.Lanier LL: NK cell receptors. Annu Rev Immunol 1998, 16:359–393.Biron CA, Gazzinelli RT: Effects of IL-12 on immune responses to microbial infections: a key mediator in regulating disease outcome. Curr Opin Immunol 1995, 7:485–496.Welsh RM, Jr.: Cytotoxic cells induced during lymphocytic choriomeningitis virus infection of mice. I. Characterization of natural killer cell induction. J Exp Med 1978, 148:163–181.da Silva IP, Gallois A, Jimenez-Baranda S, Khan S, Anderson AC, Kuchroo VK, Osman I, Bhardwaj N: Reversal of NK-cell exhaustion in advanced melanoma by Tim-3 blockade. Cancer Immunol Res 2014, 2:410–422.van Hall T, Andre P, Horowitz A, Ruan DF, Borst L, Zerbib R, Narni-Mancinelli E, van der Burg SH, Vivier E: Monalizumab: inhibiting the novel immune checkpoint NKG2A. J Immunother Cancer 2019, 7:263.Ethics ApprovalPrimary urothelial bladder cancer tumor tissue was obtained after obtaining informed consent in the context of an Institutional Review Board (IRB)-approved genitourinary cancer clinical database and specimen collection protocol (IRB #10-1180) at the Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai (New York, NY).

scholarly journals 314 NKG2A and HLA-E define a novel alternative immune checkpoint axis in bladder cancer

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A338-A338
Author(s):  
Berengere Salome ◽  
John Sfakianos ◽  
Andrew Charap ◽  
Adam Farkas ◽  
Daniel Geanon ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Immune Checkpoint ◽  
Nk Cell ◽  
Hla Class I ◽  
Cd8 T Cell ◽  
Bladder Tumors ◽  
Cell Responses

BackgroundBladder cancer is characterized by a poor prognosis, with muscle-invasive cases harboring a 34–76% 10-year recurrence-free survival rate.1 Neoadjuvant PD-1/PD-L1 blockade strategies have recently been approved by the US Food and Drug Administration for bladder cancer treatment, yet only achieving a complete response rate of 31–37%, thereby suggesting additional mechanisms of resistance.2 HLA-E is a known inhibitor of NKG2A+ CD8 T cells and NK cell responses. A monoclonal antibody binding to the NKG2A receptor has been developed and proven to restore CD8 T cell and NK cell responses in head and neck cancer, with ongoing clinical trials across multiple tumor indications.3 4 We evaluated the potential role of the HLA-E/NKG2A inhibitory pathway in modulating T cell immunity in bladder cancer.MethodsCyTOF was performed on CD8+ T cells from fresh bladder tumors (n=6), as well as on expanded CD8+ T cells from bladder-draining lymph nodes (n=11) and tumors (n=8). Flow cytometry (n=25) and single-cell RNA-sequencing (scRNAseq) (n=13) were performed on cells from fresh bladder tumors.ResultsMechanisms of tumor escape from CD8+ T cell recognition include impairment of antigen presentation. Accordingly, we found a significant reduction of HLA class I expression on tumors. However, expression of DNAM-1-activating ligands (e.g. CD112,CD155) on bladder tumors was retained, indicating a possible role for TCR-independent activation pathways traditionally ascribed to natural killer (NK) cells. Using mass cytometry and scRNAseq, we observed that acquisition of NKG2A on tumor-derived PD-1+ CD8+ T cells promotes tissue-resident memory features alongside diminished CD28 expression and significantly weaker sensitivity to CD3/CD28-signaling. However, NKG2A+ CD8 T cells possess a proliferative advantage with enhanced expression of DNAM-1 and cytolytic machinery.Strikingly, we found that NKG2A+PD-1+ CD8 T cells are strongly activated in response to HLA class I-deficient tumors compared to their NKG2A- PD-1+ CD8 T cell counterparts. TCR-independent NK-like function by NKG2A+ CD8 T cell is partly mediated by the DNAM-1 pathway and inhibited by HLA-E. NKG2A+ CD8 T cell functions are restored upon NKG2A blockade, where efficiency positively correlates with HLA-E expression on bladder tumors.ConclusionsCollectively, our data indicate that NKG2A+ CD8 T cells display a strong capacity for TCR-independent activation that enables them to circumvent bladder tumor evasion mechanisms. NKG2A+ CD8 T cells lack expression of CD28 suggesting a lower susceptibility to PD-1-mediated inhibiton. Our data suggest a need for thorough reappraisal of current protocols that assess CD8 T cell exhaustion and for strategies to restore their antitumor functions.ReferencesSanli O, Dobruch J, Knowles MA, Burger M, Alemozaffar M, Nielsen ME, Lotan Y. Bladder cancer. Nat Rev Dis Primers 2017 April 13;3:17022. doi: 10.1038/nrdp.2017.22. PMID: 28406148. Rouanne M, Bajorin DF, Hannan R, Galsky MD, Williams SB, Necchi A, Sharma P, Powles T. Rationale and outcomes for neoadjuvant immunotherapy in urothelial carcinoma of the bladder. Eur Urol Oncol 2020 December;3(6):728–738. doi: 10.1016/j.euo.2020.06.009. Epub 2020 Nov 8. PMID: 33177001. André P, Denis C, Soulas C, Bourbon-Caillet C, Lopez J, Arnoux T, Bléry M, Bonnafous C, Gauthier L, Morel A, Rossi B, Remark R, Breso V, Bonnet E, Habif G, Guia S, Lalanne AI, Hoffmann C, Lantz O, Fayette J, Boyer-Chammard A, Zerbib R, Dodion P, Ghadially H, Jure-Kunkel M, Morel Y, Herbst R, Narni-Mancinelli E, Cohen RB, Vivier E. Anti-NKG2A mAb is a checkpoint inhibitor that promotes anti-tumor immunity by unleashing both T and NK Cells. Cell 2018 December 13;175(7):1731–1743.e13. doi: 10.1016/j.cell.2018.10.014. Epub 2018 Nov 29. PMID: 30503213; PMCID: PMC6292840. van Hall T, André P, Horowitz A, Ruan DF, Borst L, Zerbib R, Narni-Mancinelli E, van der Burg SH, Vivier E. Monalizumab: inhibiting the novel immune checkpoint NKG2A. J Immunother Cancer 2019 October 17;7(1):263. doi: 10.1186/s40425-019-0761-3. PMID: 31623687; PMCID: PMC6798508.

scholarly journals Role of Recipient CD8+ T Cell Exhaustion in the Rejection of Adoptively Transferred Haploidentical NK Cells

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 503-503
Author(s):  
Robin Williams ◽  
Sarah Cooley ◽  
Veronika Bachanova ◽  
Thomas A Waldmann ◽  
Bruce R. Blazar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Cd8 T Cells ◽  
Cell Expansion ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Refractory Aml

Natural killer (NK) cells are cytotoxic innate lymphoid cells, which play a major role in tumor surveillance. We have tested the safety and efficacy of allogeneic NK cell adoptive transfer from heathy haploidentical donors and demonstrate that in vivo expansion and persistence of the adoptively transferred NK cells at Day 14 after infusion correlates with 30-50% remission in patients with refractory AML. However, the factors that influence successful persistence of donor-derived NK cells are unclear. We hypothesized that recipient T cells play a role in the rejection of allogeneic NK cells and a correlation could exist between persistence of donor-derived NK cells and exhaustion in recipient T cells. T cell exhaustion, a well-established state of T-cell dysfunction occurring in response to chronic and continuous antigen stimulation, is well-documented in human cancer, and characterized by progressive and hierarchical loss of effector functions including sustained up-regulation and co-expression of multiple inhibitory receptors such as PD-1 and Tim-3 and altered expression of key transcription factors including the gain of Eomes and T-bet. We used samples from a phase I/II trial of CD3/CD19 depleted, IL-15-activated, haploidentical donor NK cells delivered following conditioning with cyclophosphamide (50mg/kg) and fludarabine (35 mg/m2 x 3days) in adults with chemotherapy refractory AML. Patients received donor NK cells on Day 0 followed by 10 doses of recombinant human (rh) IL-15 (2 mcg/kg/day) manufactured by the NCI and delivered SQ on Days 1-5 and 8-12. A significant proportion of patients experienced donor NK cell expansion at Day 14 (expanders), but there were some that did not (non-expanders). Therapeutic benefit has only been noted among the expanders. We examined samples from a total of 10 patients with refractory AML, 5 expanders and 5 non-expanders, along with their 10 respective donors. Cryopreserved patient PBMCs were thawed and rested overnight in RPMI-1640 with 2% FBS. The cells were stained for viability, for surface markers using antibodies against CD3, CD8, CD56, PD-1, and Tim-3, intracellularly stained for Eomes and T-bet. We evaluated CD8+ T cell expression of PD-1 and Tim-3, in expanders and non-expanders, prior to chemotherapy and at Day 14. Paired donor T cells from the non-mobilized apheresis products served as controls. Prior to chemotherapy, both patient groups had equivalently elevated expression of both PD1 and Tim-3 on CD8+ T cells. However, at Day 14, the expanders had persistence of PD-1 and Tim-3 while expression on non-expander CD8+ T cells fell to donor level (Figure 1A). Furthermore, expanders had a significantly higher proportion of CD8+ T cells that either co-expressed PD-1 and Tim-3 (p=0.017) or had a PD-1high phenotype (p=0.032) at Day 14, both of which are suggestive of an exhausted state, as opposed to an activated one (Figure 1B,C). Next, we examined Eomes and T-bet expression in recipient T cells. While generally low among healthy T cell populations, as T cells become exhausted, they gain expression of these transcription factors. We looked specifically at the expression of these transcription factors in the recipient CD8+ T cell populations with the highest likelihood of being exhausted, i.e. those co-expressing PD-1 and Tim-3 or those with the PD-1high phenotype. Eomes expression in recipient PD-1high CD8+ T cells and in PD-1+Tim-3+ CD8+ T cells at Day 14 was significantly higher (p=0.01 and p=0.04, respectively) among expanders compared to non-expanders (Figure 2A,B). Likewise, T-bet expression was greater (p=0.004) among expanders in the PD-1high population (Figure 2A). There was no difference in the T-bet expression in PD-1+Tim-3+ CD8+ T cells between groups (Figure 2B). While all patients with refractory AML receiving NK cell adoptive transfer had an elevated percentage of CD8+ T cells with an exhausted phenotype prior to therapy, only patients with donor-derived NK cell expansion had persistence of the exhausted T cell phenotype at Day 14. Thus, T cell mediated rejection is a major obstacle to overcome for successful adoptive NK cell transfer which could in part be aided by a link between recipient T cell exhaustion and expansion of NK cells. This might further suggest that IL-15 reverses T cell exhaustion among those who failed to achieve donor-derived NK cell expansion. Disclosures Miller: Fate Therapeutics: Consultancy, Research Funding; Oxis Biotech: Consultancy, Other: SAB.

PD-1 up-regulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors

Blood ◽  
2007 ◽  
Vol 109 (11) ◽  
pp. 4671-4678 ◽  
Author(s):  
Ji-Yuan Zhang ◽  
Zheng Zhang ◽  
Xicheng Wang ◽  
Jun-Liang Fu ◽  
Jinxia Yao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Effector Memory ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Specific Memory ◽  
Memory Cd8 T Cell

Abstract The immunoreceptor PD-1 is significantly up-regulated on exhausted CD8+ T cells during chronic viral infections such as HIV-1. However, it remains unknown whether PD-1 expression on CD8+ T cells differs between typical progressors (TPs) and long-term nonprogressors (LTNPs). In this report, we examined PD-1 expression on HIV-specific CD8+ T cells from 63 adults with chronic HIV infection. We found that LTNPs exhibited functional HIV-specific memory CD8+ T cells with markedly lower PD-1 expression. TPs, in contrast, showed significantly up-regulated PD-1 expression that was closely correlated with a reduction in CD4 T-cell number and an elevation in plasma viral load. Importantly, PD-1 up-regulation was also associated with reduced perforin and IFN-γ production, as well as decreased HIV-specific effector memory CD8+ T-cell proliferation in TPs but not LTNPs. Blocking PD-1/PD-L1 interactions efficiently restored HIV-specific CD8+ T-cell effector function and proliferation. Taken together, these findings confirm the hypothesis that high PD-1 up-regulation mediates HIV-specific CD8+ T-cell exhaustion. Blocking the PD-1/PD-L1 pathway may represent a new therapeutic option for this disease and provide more insight into immune pathogenesis in LTNPs.

scholarly journals Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia

Blood ◽  
2011 ◽  
Vol 117 (17) ◽  
pp. 4501-4510 ◽  
Author(s):  
Qing Zhou ◽  
Meghan E. Munger ◽  
Rachelle G. Veenstra ◽  
Brenda J. Weigel ◽  
Mitsuomi Hirashima ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Acute Myelogenous Leukemia ◽  
Cd8 T Cell ◽  
Myelogenous Leukemia ◽  
T Cell Exhaustion ◽  
T Regulatory Cell ◽  
Cell Exhaustion ◽  
Acute Myelogenous

Abstract Tumor-associated immune suppression can lead to defective T cell-mediated antitumor immunity. Here, we identified a unique phenotype of exhausted T cells in mice with advanced acute myelogenous leukemia (AML). This phenotype is characterized by the coexpression of Tim-3 and PD-1 on CD8+ T cells in the liver, the major first site of AML metastases. PD-1 and Tim-3 coexpression increased during AML progression. PD-1+Tim-3+ CD8+ T cells were deficient in their ability to produce IFN-γ, TNF-α, and IL-2 in response to PD-1 ligand (PDL1) and Tim-3 ligand (galectin-9) expressing AML cells. PD-1 knockout (KO), which were partially resistant to AML challenge, up-regulated Tim-3 during AML progression and such Tim-3+PD-1- KO CD8+ T cells had reduced cytokine production. Galectin-9 KO mice were more resistant to AML, which was associated with reduced T-regulatory cell accumulation and a modest induction of PD-1 and Tim-3 expression on CD8+ T cells. Whereas blocking the PD-1/PDL1 or Tim-3/galectin-9 pathway alone was insufficient to rescue mice from AML lethality, an additive effect was seen in reducing—albeit not eliminating—both tumor burden and lethality when both pathways were blocked. Therefore, combined PD-1/PDL1 and Tim-3/galectin-9 blockade may be beneficial in preventing CD8+ T-cell exhaustion in patients with hematologic malignancies such as advanced AML.

scholarly journals Inverted CD8 T-Cell Exhaustion and Co-Stimulation Marker Balance Differentiate Aviremic HIV-2-Infected From Seronegative Individuals

2021 ◽  
Vol 12 ◽  
Author(s):  
Lydia Scharf ◽  
Christina B. Pedersen ◽  
Emil Johansson ◽  
Jacob Lindman ◽  
Lars R. Olsen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Disease Progression ◽  
Cd8 T Cells ◽  
Therapy Monitoring ◽  
Expression Patterns ◽  
Cd8 T Cell ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Hiv 1

HIV-2 is less pathogenic compared to HIV-1. Still, disease progression may develop in aviremic HIV-2 infection, but the driving forces and mechanisms behind such development are unclear. Here, we aimed to reveal the immunophenotypic pattern associated with CD8 T-cell pathology in HIV-2 infection, in relation to viremia and markers of disease progression. The relationships between pathological differences of the CD8 T-cell memory population and viremia were analyzed in blood samples obtained from an occupational cohort in Guinea-Bissau, including HIV-2 viremic and aviremic individuals. For comparison, samples from HIV-1- or dually HIV-1/2-infected and seronegative individuals were obtained from the same cohort. CD8 T-cell exhaustion was evaluated by the combined expression patterns of activation, stimulatory and inhibitory immune checkpoint markers analyzed using multicolor flow cytometry and advanced bioinformatics. Unsupervised multidimensional clustering analysis identified a cluster of late differentiated CD8 T-cells expressing activation (CD38+, HLA-DRint/high), co-stimulatory (CD226+/-), and immune inhibitory (2B4+, PD-1high, TIGIThigh) markers that distinguished aviremic from viremic HIV-2, and treated from untreated HIV-1-infected individuals. This CD8 T-cell population displayed close correlations to CD4%, viremia, and plasma levels of IP-10, sCD14 and beta-2 microglobulin in HIV-2 infection. Detailed analysis revealed that aviremic HIV-2-infected individuals had higher frequencies of exhausted TIGIT+ CD8 T-cell populations lacking CD226, while reduced percentage of stimulation-receptive TIGIT-CD226+ CD8 T-cells, compared to seronegative individuals. Our results suggest that HIV-2 infection, independent of viremia, skews CD8 T-cells towards exhaustion and reduced co-stimulation readiness. Further knowledge on CD8 T-cell phenotypes might provide help in therapy monitoring and identification of immunotherapy targets.

scholarly journals IL-10 Induces T Cell Exhaustion During Transplantation of Virus Infected Hearts

2016 ◽  
Vol 38 (3) ◽  
pp. 1171-1181 ◽  
Author(s):  
Asmae Gassa ◽  
Fu Jian ◽  
Halime Kalkavan ◽  
Vikas Duhan ◽  
Nadine Honke ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Organ Transplantation ◽  
Cd8 T Cells ◽  
Immune Activation ◽  
Graft Failure ◽  
Cd8 T Cell ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

Background/Aims: Unexpected transmissions of viral pathogens during solid organ transplantation (SOT) can result in severe, life-threatening diseases in transplant recipients. Immune activation contributes to disease onset. However mechanisms balancing the immune response against transmitted viral infection through organ transplantation remain unknown. Methods & Results: Here we found, using lymphocytic choriomeningitis virus (LCMV), that transplantation of LCMV infected hearts led to exhaustion of virus specific CD8+ T cells, viral persistence in organs and survival of graft and recipient. Genetic depletion of Interleukin-10 (IL-10) resulted in strong immune activation, graft dysfunction and death of mice, suggesting that IL-10 was a major regulator of CD8+ T cell exhaustion during SOT. In the presence of memory CD8+ T cells, virus could be controlled. However sufficient antiviral immune response resulted in acute rejection of transplanted heart. Conclusion: We found that virus transmitted via SOT could not be controlled by naïve mice recipients due to IL-10 mediated CD8+ T cell exhaustion which thereby prevented immunopathology and graft failure whereas memory mice recipients were able to control the virus and induced graft failure.

scholarly journals TOX defines the degree of CD8+ T cell dysfunction in distinct phases of chronic HBV infection

Gut ◽  
2020 ◽  
pp. gutjnl-2020-322404
Author(s):  
Kathrin Heim ◽  
Benedikt Binder ◽  
Sagar ◽  
Dominik Wieland ◽  
Nina Hensel ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Hbv Infection ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Cell Dysfunction ◽  
Chronic Hepatitis B Virus ◽  
T Cell Dysfunction

ObjectiveChronic hepatitis B virus (HBV) infection is characterised by HBV-specific CD8+ T cell dysfunction that has been linked to Tcell exhaustion, a distinct differentiation programme associated with persisting antigen recognition. Recently, Thymocyte Selection-Associated High Mobility Group Box (TOX) was identified as master regulator of CD8+ T cell exhaustion. Here, we addressed the role of TOX in HBV-specific CD8+ T cell dysfunction associated with different clinical phases of infection.DesignWe investigated TOX expression in HBV-specific CD8+ T cells from 53 HLA-A*01:01, HLA-A*11:01 and HLA-A*02:01 positive patients from different HBV infection phases and compared it to hepatitis C virus (HCV)-specific, cytomegalovirus (CMV)-specific, Epstein-Barr virus (EBV)-specific and influenza virus (FLU)-specific CD8+ T cells. Phenotypic and functional analyses of virus-specific CD8+ T cells were performed after peptide-loaded tetramer-enrichment and peptide-specific expansion.ResultsOur results show that TOX expression in HBV-specific CD8+ T cells is linked to chronic antigen stimulation, correlates with viral load and is associated with phenotypic and functional characteristics of T-cell exhaustion. In contrast, similar TOX expression in EBV-specific and CMV-specific CD8+ T cells is not linked to T-cell dysfunction suggesting different underlying programmes. TOX expression in HBV-specific CD8+ T cells is also affected by targeted antigens, for example, core versus polymerase. In HBV-specific CD8+ T cells, TOX expression is maintained after spontaneous or therapy-mediated viral control in chronic but not self-limiting acute HBV infection indicating a permanent molecular imprint after chronic but not temporary stimulation.ConclusionOur data highlight TOX as biomarker specific for dysfunctional virus-specific CD8+ T cells in the context of an actively persisting infection.

scholarly journals Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells

2015 ◽  
Vol 212 (7) ◽  
pp. 1125-1137 ◽  
Author(s):  
Pamela M. Odorizzi ◽  
Kristen E. Pauken ◽  
Michael A. Paley ◽  
Arlene Sharpe ◽  
E. John Wherry
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Lymphocytic Choriomeningitis ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Cell Dysfunction ◽  
T Cell Dysfunction ◽  
T Cell Survival

Programmed Death-1 (PD-1) has received considerable attention as a key regulator of CD8+ T cell exhaustion during chronic infection and cancer because blockade of this pathway partially reverses T cell dysfunction. Although the PD-1 pathway is critical in regulating established “exhausted” CD8+ T cells (TEX cells), it is unclear whether PD-1 directly causes T cell exhaustion. We show that PD-1 is not required for the induction of exhaustion in mice with chronic lymphocytic choriomeningitis virus (LCMV) infection. In fact, some aspects of exhaustion are more severe with genetic deletion of PD-1 from the onset of infection. Increased proliferation between days 8 and 14 postinfection is associated with subsequent decreased CD8+ T cell survival and disruption of a critical proliferative hierarchy necessary to maintain exhausted populations long term. Ultimately, the absence of PD-1 leads to the accumulation of more cytotoxic, but terminally differentiated, CD8+ TEX cells. These results demonstrate that CD8+ T cell exhaustion can occur in the absence of PD-1. They also highlight a novel role for PD-1 in preserving TEX cell populations from overstimulation, excessive proliferation, and terminal differentiation.

scholarly journals Interplay between regulatory T cells and PD-1 in modulating T cell exhaustion and viral control during chronic LCMV infection

2014 ◽  
Vol 211 (9) ◽  
pp. 1905-1918 ◽  
Author(s):  
Pablo Penaloza-MacMaster ◽  
Alice O. Kamphorst ◽  
Andreas Wieland ◽  
Koichi Araki ◽  
Smita S. Iyer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Depletion ◽  
T Cell Exhaustion ◽  
Viral Control ◽  
Cell Exhaustion ◽  
Cell Ablation ◽  
Infected Cells

Regulatory T (T reg) cells are critical for preventing autoimmunity mediated by self-reactive T cells, but their role in modulating immune responses during chronic viral infection is not well defined. To address this question and to investigate a role for T reg cells in exhaustion of virus-specific CD8 T cells, we depleted T reg cells in mice chronically infected with lymphocytic choriomeningitis virus (LCMV). T reg cell ablation resulted in 10–100-fold expansion of functional LCMV-specific CD8 T cells. Rescue of exhausted CD8 T cells was dependent on cognate antigen, B7 costimulation, and conventional CD4 T cells. Despite the striking recovery of LCMV-specific CD8 T cell responses, T reg cell depletion failed to diminish viral load. Interestingly, T reg cell ablation triggered up-regulation of the molecule programmed cell death ligand-1 (PD-L1), which upon binding PD-1 on T cells delivers inhibitory signals. Increased PD-L1 expression was observed especially on LCMV-infected cells, and combining T reg cell depletion with PD-L1 blockade resulted in a significant reduction in viral titers, which was more pronounced than that upon PD-L1 blockade alone. These results suggest that T reg cells effectively maintain CD8 T cell exhaustion, but blockade of the PD-1 inhibitory pathway is critical for elimination of infected cells.

scholarly journals NFAT-dependent and -independent exhaustion circuits program maternal CD8 T cell hypofunction in pregnancy

2021 ◽  
Vol 219 (1) ◽  
Author(s):  
Emma L. Lewis ◽  
Rong Xu ◽  
Jean-Christophe Beltra ◽  
Shin Foong Ngiow ◽  
Jordana Cohen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Ribosomal Proteins ◽  
Molecular Mechanisms ◽  
Cd8 T Cell ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Fetal Antigen ◽  
In Pregnancy

Pregnancy is a common immunization event, but the molecular mechanisms and immunological consequences provoked by pregnancy remain largely unknown. We used mouse models and human transplant registry data to reveal that pregnancy induced exhausted CD8 T cells (Preg-TEX), which associated with prolonged allograft survival. Maternal CD8 T cells shared features of exhaustion with CD8 T cells from cancer and chronic infection, including transcriptional down-regulation of ribosomal proteins and up-regulation of TOX and inhibitory receptors. Similar to other models of T cell exhaustion, NFAT-dependent elements of the exhaustion program were induced by fetal antigen in pregnancy, whereas NFAT-independent elements did not require fetal antigen. Despite using conserved molecular circuitry, Preg-TEX cells differed from TEX cells in chronic viral infection with respect to magnitude and dependency of T cell hypofunction on NFAT-independent signals. Altogether, these data reveal the molecular mechanisms and clinical consequences of maternal CD8 T cell hypofunction and identify pregnancy as a previously unappreciated context in which T cell exhaustion may occur.

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