scholarly journals Multi-Dimensional Analysis of Immune Signature Predicts Response to Decitabine Treatment in Elderly Patients with AML

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1526-1526
Author(s):  
Chenchen Zhao ◽  
Bei Jia ◽  
Liru Wang ◽  
David F. Claxton ◽  
W. Christopher Ehmann ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Clinical Outcome ◽  
Cd8 T Cells ◽  
Immune Status ◽  
Granzyme B ◽  
Cd8 T Cell ◽  
Immune Signature ◽  
Ifn Γ

Abstract Treatment for elderly AML patients who are unfit for intensive chemotherapy remains challenging. Induction with hypomethylating agents (HMA) are the most commonly used approach, however the rate of complete remission (CR) is only around 20% and median survival of 7-12 months. Clearly how to improve the clinical outcome in this patient population is an unmet need. Immunotherapy is promising in cancer treatment. A recent study demonstrated that HMA enhanced PD-1 pathway in MDS and AML patients (Yang et al., Leukemia 2014), suggesting a role of combining HMA and immunotherapy in leukemia therapeutics. To optimize this strategy, it is crucial to understand the interaction between HMA and immune response in AML. Here we performed both phenotypic and functional analysis on clinical samples collected from AML patients undergoing treatment of decitabine (DAC), a broadly used HMA. We aim to determine 1) how DAC influences the immune system; and 2) whether the immune status in AML patients predict the response to DAC treatment. Total of 22 peripheral blood samples from 11 AML patients receiving DAC were examined. Samples were collected at the time of prior to and 1-month post DAC treatment. We conducted a comprehensive phenotypic analysis of immune markers characterizing each immune component (T cells, B cells, NK, NKT, monocytes, myeloid-derived suppressor cells, and dendritic cells) and expression patterns of co-stimulatory or inhibitory molecules. In addition, perforin, granzyme B and cytokine release in response to anti-CD3/CD28 stimulation were examined to determine the functional status of T cells. A total of 45 markers separated in 8 overlapped staining panels were tested by flow cytometry. We first assessed the impact of DAC on the immune response in AML. Comparing the paired samples prior to vs. post treatment from the same patients, we observed an increase of the percentage of NK cells, as well as their expression of granzyme B and perforin upon DAC treatment. In contrast, DAC appears to cause CD8 T cell suppression as CD8 T cells from post-DAC samples showed higher PD-1 expression whereas lower IFN-γ production. We next investigated the predictive value of immune status for the response to DAC treatment. Among the 18 evaluable samples, we defined 10 responders (CR/Cri/PR) vs. 8 non-responders (treatment failure) based on the ELN 2017 recommendations. The correlation of immune characteristics to the clinical response was carefully examined. We started with an unsupervised principal component analysis (PCA), which revealed a distinguished pattern between the responders and non-responders (Fig. 1A). This encouraging observation suggests an association of immune signature to clinical outcome. Subsequent analysis demonstrated a major contribution of CD8 T cells to the association. We then focused on the phenotypic and functional analysis of CD8 T cells in responders vs. non-responders. We found a significantly higher percentage of terminal differentiated cells in non-responders compared with that of responders. Importantly, in the perspective of phenotypes, hierarchical clustering on markers of CD8 T cells divided samples into two major clades, 7 of 8 samples (87.5%) were responders on one branch and 7 of 10 samples (70%) were non-responders on the other. Most responders expressed lower frequency of inhibitory receptors and higher frequency of stimulatory receptors, whereas non-responders showed the opposite trend (Fig. 1B). The significant difference of these receptors was validated in paired t test analysis. Functional studies also showed more IFN-γ production in responders. Interestingly the intracellular staining of perforin and granzyme B was higher in non-responders, likely due to exhausted T cells that are unable to release these particles extracellularly. Collectively, our study discovered the vital role of the immune signature in predicting clinical outcome in AML. High functional CD8 T cell status, manifested by more capability of IFN-γ production, enhanced stimulatory molecule and low inhibitory receptor expression, associated with effective clinical response to DAC treatment. In addition, CD8 T cell function was down-regulated upon DAC treatment. Our results provide a strong rationale for integrating immunotherapy into HMA treatment in AML, also highlight the importance of immune signature analysis in the future trial design for this clinical setting. Disclosures No relevant conflicts of interest to declare.

scholarly journals IL-1 enhances expansion, effector function, tissue localization, and memory response of antigen-specific CD8 T cells

2013 ◽  
Vol 210 (3) ◽  
pp. 491-502 ◽  
Author(s):  
Shlomo Z. Ben-Sasson ◽  
Alison Hogg ◽  
Jane Hu-Li ◽  
Paul Wingfield ◽  
Xi Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Granzyme B ◽  
Interleukin 1 ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
In Vivo Models ◽  
Ifn Γ

Here, we show that interleukin-1 (IL-1) enhances antigen-driven CD8 T cell responses. When administered to recipients of OT-I T cell receptor transgenic CD8 T cells specific for an ovalbumin (OVA) peptide, IL-1 results in an increase in the numbers of wild-type but not IL1R1−/− OT-I cells, particularly in spleen, liver, and lung, upon immunization with OVA and lipopolysaccharide. IL-1 administration also results in an enhancement in the frequency of antigen-specific cells that are granzyme B+, have cytotoxic activity, and/ or produce interferon γ (IFN-γ). Cells primed in the presence of IL-1 display enhanced expression of granzyme B and increased capacity to produce IFN-γ when rechallenged 2 mo after priming. In three in vivo models, IL-1 enhances the protective value of weak immunogens. Thus, IL-1 has a marked enhancing effect on antigen-specific CD8 T cell expansion, differentiation, migration to the periphery, and memory.

scholarly journals Organ- and Disease-Stage-Specific Regulation of Toxoplasma gondii-Specific CD8-T-Cell Responses by CD4 T Cells

2006 ◽  
Vol 74 (10) ◽  
pp. 5790-5801 ◽  
Author(s):  
Sonja Lütjen ◽  
Sabine Soltek ◽  
Simona Virna ◽  
Martina Deckert ◽  
Dirk Schlüter
Keyword(s):  
T Cells ◽  
T Cell ◽  
Toxoplasma Gondii ◽  
Cd8 T Cells ◽  
Functional Activity ◽  
Cd4 T Cells ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Ifn Γ

ABSTRACT Toxoplasma gondii induces a persistent central nervous system infection, which may be lethally reactivated in AIDS patients with low CD4 T-cell numbers. To analyze the role of CD4 T cells for the regulation of parasite-specific CD8 T cells, mice were infected with transgenic T. gondii expressing the CD8 T-cell antigen β-galactosidase (β-Gal). Depletion of CD4 T cells prior to infection did not affect frequencies of β-Gal876-884-specific (consisting of residues 876 to 884 of β-Gal) CD8 T cells but resulted in a pronounced reduction of intracerebral β-Gal-specific gamma interferon (IFN-γ)-producing and cytolytic CD8 T cells. After cessation of anti-CD4 treatment a normal T. gondii-specific CD4 T-cell response developed, but IFN-γ production of intracerebral β-Gal-specific CD8 T cells remained impaired. The important supportive role of CD4 T cells for the optimal functional activity of intracerebral CD8 T cells was also observed in mice that had been depleted of CD4 T cells during chronic toxoplasmosis. Reinfection of chronically infected mice that had been depleted of CD4 T cells during either the acute or chronic stage of infection resulted in an enhanced proliferation of β-Gal-specific IFN-γ-producing splenic CD8 T cells. However, reinfection of chronically infected mice that had been depleted of CD4 T cells in the acute stage of infection did not reverse the impaired IFN-γ production of intracerebral CD8 T cells. Collectively, these findings illustrate that CD4 T cells are not required for the induction and maintenance of parasite-specific CD8 T cells but, depending on the stage of infection, the infected organ and parasite challenge infection regulate the functional activity of intracerebral CD8 T cells.

Clonal Expansion of Graft-Versus-Host Reactive CD8+ T Cells Is Dissociated from Full Effector Differentiation Following Delayed DLI.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2170-2170
Author(s):  
Ronjon Chakraverty ◽  
Barry Flutter ◽  
Hyeon-Seok Eom ◽  
Farnaz Fallah-Arani ◽  
Guiling Zhao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Population ◽  
Cd8 T Cells ◽  
Granzyme B ◽  
Cd8 T Cell ◽  
Host Environment ◽  
Graft Versus Host ◽  
Donor T Cells ◽  
Ifn Γ

Abstract Extrinsic factors within the host environment are crucial in determining recruitment of graft-versus-host (GVH)-reactive T cells to peripheral tissues and the capacity of these cells to induce graft-versus-host disease (GVHD). In this study, we have examined how the host environment influences graft-versus-leukemia (GVL) activity. Transfer of small numbers of allogeneic T cells to freshly irradiated (TBI allo) mice induces both GVL and GVHD, whereas transfer of much higher numbers of T cells to established (>8 weeks) mixed chimeras (MC) can induce GVL without GVHD. Using an EL4 tumor protection assay and low doses of B10.A splenocytes (3 × 10e6, a dose 1 log lower than normally transferred to MC to induce GVL), we observed that tumor-free survival of recipient mice was greater following transfer to TBI allo B6 recipients than in B6 + B10.A → B6 MC. To determine the mechanisms for this disparity, we used a BALB/c recipient/B6 donor strain combination, in which we could track the distribution of donor T cells within secondary lymphoid organs and bone marrow (BM) following transfer to TBI allo or MC recipients. Despite similar expansions within the spleen, there was a significant delay in the accumulation of polyclonal donor T cells (B6 CD45.1) and transgenic 2C GVH-reactive CD8+ T-cells (bearing TCR specific for recipient antigen) in the BM of MC compared to TBI allo mice. Moreover, in vivo cytotoxicity of host B cell targets occurred rapidly and was virtually complete in TBI allo recipients, but was absent in MC even at late time points. To evaluate the acquisition of effector functions in a clonal GVH-reactive CD8+ T cell population, we sorted 2C T cells at intervals following transfer and performed quantitative RT-PCR of molecules linked to effector differentiation. Strikingly, transcription of IFN-γ, granzyme B and TNF-α was significantly higher in cells derived from TBI allo hosts compared to MC. Similar differences in IFN-γ and granzyme B protein expression were confirmed in the polyclonal donor CD8+ T cell population. Since, full GVL activity might also depend upon the survival of GVH-reactive CTL, we also examined the viability of donor T cells during the initial response in both environments. We observed higher rates of sustained 2C CD8+ T cell apoptosis (as indicated by annexin V staining) following T cell transfer to MC. Furthermore, we also detected lower expression of common γ chain cytokine receptors that mediate responsiveness to IL-2, IL-7 and IL-15, upon donor T cells from MC. However, following secondary co-transfer to syngeneic recipients for 21 days, memory phenotype polyclonal donor CD8+ T cells derived from established MC (CD45.1+) were recovered to a greater extent than T cells initially derived from TBI allo mice (Thy1.1+), arguing against any intrinsic defect in the viability of GVH-reactive T cell populations emerging in the former setting. Indeed, when co-cultured in the presence of individual cytokines, MC-derived CD8+ T cells maintained viability to a greater (IL-2, IL-7) or equivalent (IL-15) extent as TBI allo-derived cells. Taken together, these data suggest that disparity in GVL activity following to TBI allo recipients and MC can be explained by differences in the effector function and survival of anti-host CTL in quiescent MC environment. Reduced GVL activity of donor T cells on a per-cell basis in MC can be compensated for by transferring greater numbers of cells.

scholarly journals Treatment with Soluble Interleukin-15Rα Exacerbates Intracellular Parasitic Infection by Blocking the Development of Memory CD8+ T Cell Response

2002 ◽  
Vol 195 (11) ◽  
pp. 1463-1470 ◽  
Author(s):  
Imtiaz A. Khan ◽  
Magali Moretto ◽  
Xiao-qing Wei ◽  
Martha Williams ◽  
Joseph D. Schwartzman ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Response ◽  
Parasitic Infection ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Memory Cd8 T Cells ◽  
Ifn Γ

Interferon (IFN)-γ–producing CD8+ T cells are important for the successful resolution of the obligate intracellular parasite Toxoplasma gondii by preventing the reactivation or controlling a repeat infection. Previous reports from our laboratory have shown that exogenous interleukin (IL)-15 treatment augments the CD8+ T cell response against the parasite. However, the role of endogenous IL-15 in the proliferation of activated/memory CD8+ T cells during toxoplasma or any other infection is unknown. In this study, we treated T. gondii immune mice with soluble IL-15 receptor α (sIL-15Rα) to block the host endogenous IL-15. The treatment markedly reduced the ability of the immune animals to control a lethal infection. CD8+ T cell activities in the sIL-15Rα–administered mice were severely reduced as determined by IFN-γ release and target cell lysis assays. The loss of CD8+ T cell immunity due to sIL-15Rα treatment was further demonstrated by adoptive transfer experiments. Naive recipients transferred with CD44hi activated/memory CD8+ T cells and treated with sIL-15Rα failed to resist a lethal T. gondii infection. Moreover, sIL-15Rα treatment of the recipients blocked the ability of donor CD44hi activated/memory CD8+ T cells to replicate in response to T. gondii challenge. To our knowledge, this is the first demonstration of the important role of host IL-15 in the development of antigen-specific memory CD8+ T cells against an intracellular infection.

scholarly journals Type I Interferons Are Essential in Controlling Neurotropic Coronavirus Infection Irrespective of Functional CD8 T Cells

2007 ◽  
Vol 82 (1) ◽  
pp. 300-310 ◽  
Author(s):  
Derek D. C. Ireland ◽  
Stephen A. Stohlman ◽  
David R. Hinton ◽  
Roscoe Atkinson ◽  
Cornelia C. Bergmann
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Replication ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Type I ◽  
Virus Variant ◽  
Coronavirus Infection ◽  
Ifn Γ

ABSTRACT Neurotropic coronavirus infection induces expression of both beta interferon (IFN-β) RNA and protein in the infected rodent central nervous system (CNS). However, the relative contributions of type I IFN (IFN-I) to direct, cell-type-specific virus control or CD8 T-cell-mediated effectors in the CNS are unclear. IFN-I receptor-deficient (IFNAR−/−) mice infected with a sublethal and demyelinating neurotropic virus variant and those infected with a nonpathogenic neurotropic virus variant both succumbed to infection within 9 days. Compared to wild-type (wt) mice, replication was prominently increased in all glial cell types and spread to neurons, demonstrating expanded cell tropism. Furthermore, increased pathogenesis was associated with significantly enhanced accumulation of neutrophils, tumor necrosis factor alpha, interleukin-6, chemokine (C-C motif) ligand 2, and IFN-γ within the CNS. The absence of IFN-I signaling did not impair induction or recruitment of virus-specific CD8 T cells, the primary adaptive mediators of virus clearance in wt mice. Despite similar IFN-γ-mediated major histocompatibility complex class II upregulation on microglia in infected IFNAR−/− mice, class I expression was reduced compared to that on microglia in wt mice, suggesting a synergistic role of IFN-I and IFN-γ in optimizing class I antigen presentation. These data demonstrate a critical direct antiviral role of IFN-I in controlling virus dissemination within the CNS, even in the presence of potent cellular immune responses. By limiting early viral replication and tropism, IFN-I controls the balance of viral replication and immune control in favor of CD8 T-cell-mediated protective functions.

scholarly journals Virally Activated CD8 T Cells Home to Mycobacterium bovis BCG-Induced Granulomas but Enhance Antimycobacterial Protection Only in Immunodeficient Mice

2006 ◽  
Vol 75 (3) ◽  
pp. 1154-1166 ◽  
Author(s):  
Laura H. Hogan ◽  
Dominic O. Co ◽  
Jozsef Karman ◽  
Erika Heninger ◽  
M. Suresh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mycobacterium Bovis ◽  
Cd8 T Cells ◽  
Bacterial Load ◽  
Granulomatous Inflammation ◽  
Cd8 T Cell ◽  
Activated T Cells ◽  
Immunodeficient Mice ◽  
Ifn Γ

ABSTRACT The effect of secondary infections on CD4 T-cell-regulated chronic granulomatous inflammation is not well understood. Here, we have investigated the effect of an acute viral infection on the cellular composition and bacterial protection in Mycobacterium bovis strain bacille Calmette-Guérin (BCG)-induced granulomas using an immunocompetent and a partially immunodeficient murine model. Acute lymphocytic choriomeningitis virus (LCMV) coinfection of C57BL/6 mice led to substantial accumulation of gamma interferon (IFN-γ)-producing LCMV-specific T cells in liver granulomas and increased local IFN-γ. Despite traffic of activated T cells that resulted in a CD8 T-cell-dominated granuloma, the BCG liver organ load was unaltered from control levels. In OT-1 T-cell-receptor (TCR) transgenic mice, ovalbumin (OVA) immunization or LCMV coinfection of BCG-infected mice induced CD8 T-cell-dominated granulomas containing large numbers of non-BCG-specific activated T cells. The higher baseline BCG organ load in this CD8 TCR transgenic animal allowed us to demonstrate that OVA immunization and LCMV coinfection increased anti-BCG protection. The bacterial load remained substantially higher than in mice with a more complete TCR repertoire. Overall, the present study suggests that peripherally activated CD8 T cells can be recruited to chronic inflammatory sites, but their contribution to protective immunity is limited to conditions of underlying immunodeficiency.

scholarly journals 677 Reverse abscopal effect: intertumoral heterogeneity suppresses systemic CD8 T cell-mediated antitumor immunity and confers PD-1 inhibitor resistance in synchronous melanoma

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A705-A705
Author(s):  
Shuyang Qin ◽  
Booyeon Han ◽  
Alexander Chacon ◽  
Alexa Melucci ◽  
Alyssa Williams ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Line ◽  
Cd8 T Cells ◽  
Antitumor Immunity ◽  
Immune Escape ◽  
Cd8 T Cell ◽  
Abscopal Effect ◽  
Immunogenic Tumor ◽  
Ifn Γ

BackgroundDespite recent advancements in systemic therapy, only a minority of metastatic patients develop meaningful clinical responses to immune checkpoint inhibitors. Inherent genetic instability of melanoma generates genomically and microenvironmentally distinct metastases. These different tumor microenvironments (TMEs) contain numerous T cell suppression mechanisms, such as upregulation of the PD-1/PD-L1 exhaustion pathway. However, as synchronous metastases share one host immune system, intertumoral heterogeneity may result in increasing cross-talk between metastases that impairs systemic antitumor immunity and promotes PD-1 immunotherapy resistance.MethodsYUMM 1.7 (less immunogenic) and YUMMER 1.7 (more immunogenic cell line derived from YUMM following UVB irradiation) melanoma cell lines were simultaneously injected into opposite flanks of the same mice as a model of synchronous melanoma. We assessed tumor growth in wildtype, interferon-gamma (IFN-γ) knockout, and CD8-depleted mice as well as in response to PD-1 inhibitor. We characterized the TME with flow cytometry and performed TCR sequencing on tumor-infiltrating CD8 T cells.ResultsDistinct TMEs were observed for YUMM and YUMMER tumors simultaneously grown in the same mouse. The presence of the less immunogenic YUMM tumor allows the more immunogenic YUMMER tumors to escape IFN-γ and CD8 T cell-mediated rejection, despite abundant tumor-infiltrating, clonally expanded CD8 T cells. Identical immunodominant CD8 T cell clones were found in both YUMM and YUMMER tumors within the same mouse. Synchronous YUMMER-infiltrating CD8 T cells exhibit suppressed phenotypes, including increased persistence of surface PD-1 and decreased surface CD107a expressions. Simultaneously, these synchronous YUMMER tumors additionally upregulate macrophage surface PD-L1 expression, which potentially contributes to tumor immune escape. Lastly, synchronous YUMMER tumors become resistant to PD-1 inhibition, in direct contrast to control YUMMER tumors.ConclusionsIn a host with multiple melanoma lesions, immunogenicity of all tumors contribute to the systemic antitumor immune response. We show that two synchronous tumors with synonymous mutations (<40%), as is the case with metastatic patients, lead to skewed CD8 T cell expansion of the same clones in both tumors. The presence of a less immunogenic tumor prevents CD8 and IFN-γ mediated rejection of the more immunogenic tumor. Furthermore, CD8 T cells in the more immunogenic tumor exhibit decreased effector function and increased resistance to PD-1 blockade, as tumor-infiltrating macrophages concurrently become more immunosuppressive. These results are highly suggestive of a “reverse abscopal effect,” by which immunologically “cold” tumors generate systemic immunosuppression that facilitate PD-1 immunotherapy resistance and immune escape of all other tumors in synchronous metastatic melanoma patients.AcknowledgementsWe would like to thank Dr. Marcus Bosenberg from the Department of Dermatology at Yale University for kindly gifting us with the YUMMER 1.7 murine melanoma cell line.Ethics ApprovalAnimal experiments were approved by the University Committee on Animal Resources and performed in accordance with University of Rochester approved guidelines.

scholarly journals Generation of Human CD8 T Regulatory Cells by CD40 Ligand–activated Plasmacytoid Dendritic Cells

2002 ◽  
Vol 195 (6) ◽  
pp. 695-704 ◽  
Author(s):  
Michel Gilliet ◽  
Yong-Jun Liu
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Transforming Growth Factor ◽  
Cd8 T Cell ◽  
Cd40 Ligand ◽  
Plasmacytoid Dendritic Cells ◽  
Target Cells ◽  
Ifn Γ

Although CD8 T cell–mediated immunosuppression has been a well-known phenomenon during the last three decades, the nature of primary CD8 T suppressor cells and the mechanism underlying their generation remain enigmatic. We demonstrated that naive CD8 T cells primed with allogeneic CD40 ligand–activated plasmacytoid dendritic cells (DC)2 differentiated into CD8 T cells that displayed poor secondary proliferative and cytolytic responses. By contrast, naive CD8 T cells primed with allogeneic CD40 ligand–activated monocyte-derived DCs (DC1) differentiated into CD8 T cells, which proliferated to secondary stimulation and killed allogeneic target cells. Unlike DC1-primed CD8 T cells that produced large amounts of interferon (IFN)-γ upon restimulation, DC2-primed CD8 T cells produced significant amounts of interleukin (IL)-10, low IFN-γ, and no IL-4, IL-5, nor transforming growth factor (TGF)-β. The addition of anti–IL-10–neutralizing monoclonal antibodies during DC2 and CD8 T cell coculture, completely blocked the generation of IL-10–producing anergic CD8 T cells. IL-10–producing CD8 T cells strongly inhibit the allospecific proliferation of naive CD8 T cells to monocytes, and mature and immature DCs. This inhibition was mediated by IL-10, but not by TGF-β. IL-10–producing CD8 T cells could inhibit the bystander proliferation of naive CD8 T cells, provided that they were restimulated nearby to produce IL-10. IL-10–producing CD8 T cells could not inhibit the proliferation of DC1-preactivated effector T cells. This study demonstrates that IL-10–producing CD8 T cells are regulatory T cells, which provides a cellular basis for the phenomenon of CD8 T cell–mediated immunosuppression and suggests a role for plasmacytoid DC2 in immunological tolerance.

scholarly journals Role of PD-1 during effector CD8 T cell differentiation

2018 ◽  
Vol 115 (18) ◽  
pp. 4749-4754 ◽  
Author(s):  
Eunseon Ahn ◽  
Koichi Araki ◽  
Masao Hashimoto ◽  
Weiyan Li ◽  
James L. Riley ◽  
...  
Keyword(s):  
T Cells ◽  
Cell Differentiation ◽  
T Cell ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Cell Epitope ◽  
Cd8 T Cell ◽  
T Cell Differentiation ◽  
Lcmv Infection

PD-1 (programmed cell death-1) is the central inhibitory receptor regulating CD8 T cell exhaustion during chronic viral infection and cancer. Interestingly, PD-1 is also expressed transiently by activated CD8 T cells during acute viral infection, but the role of PD-1 in modulating T cell effector differentiation and function is not well defined. To address this question, we examined the expression kinetics and role of PD-1 during acute lymphocytic choriomeningitis virus (LCMV) infection of mice. PD-1 was rapidly up-regulated in vivo upon activation of naive virus-specific CD8 T cells within 24 h after LCMV infection and in less than 4 h after peptide injection, well before any cell division had occurred. This rapid PD-1 expression by CD8 T cells was driven predominantly by antigen receptor signaling since infection with a LCMV strain with a mutation in the CD8 T cell epitope did not result in the increase of PD-1 on antigen-specific CD8 T cells. Blockade of the PD-1 pathway using anti–PD-L1 or anti–PD-1 antibodies during the early phase of acute LCMV infection increased mTOR signaling and granzyme B expression in virus-specific CD8 T cells and resulted in faster clearance of the infection. These results show that PD-1 plays an inhibitory role during the naive-to-effector CD8 T cell transition and that the PD-1 pathway can also be modulated at this stage of T cell differentiation. These findings have implications for developing therapeutic vaccination strategies in combination with PD-1 blockade.

scholarly journals Chronic Hepatitis C Virus Infection Impairs M1 Macrophage Differentiation and Contributes to CD8+ T-Cell Dysfunction

Cells ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 374 ◽  
Author(s):  
Faria Ahmed ◽  
Andrea Ibrahim ◽  
Curtis L. Cooper ◽  
Ashok Kumar ◽  
Angela M. Crawley
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Hcv Infection ◽  
M1 Macrophage ◽  
T Cell Dysfunction ◽  
Chronic Hcv Infection ◽  
Ifn Γ ◽  
Chronic Hcv

Chronic hepatitis C virus (HCV) infection causes generalized CD8+ T cell impairment, not limited to HCV-specific CD8+ T-cells. Liver-infiltrating monocyte-derived macrophages (MDMs) contribute to the local micro-environment and can interact with and influence cells routinely trafficking through the liver, including CD8+ T-cells. MDMs can be polarized into M1 (classically activated) and M2a, M2b, and M2c (alternatively activated) phenotypes that perform pro- and anti-inflammatory functions, respectively. The impact of chronic HCV infection on MDM subset functions is not known. Our results show that M1 cells generated from chronic HCV patients acquire M2 characteristics, such as increased CD86 expression and IL-10 secretion, compared to uninfected controls. In contrast, M2 subsets from HCV-infected individuals acquired M1-like features by secreting more IL-12 and IFN-γ. The severity of liver disease was also associated with altered macrophage subset differentiation. In co-cultures with autologous CD8+ T-cells from controls, M1 macrophages alone significantly increased CD8+ T cell IFN-γ expression in a cytokine-independent and cell-contact-dependent manner. However, M1 macrophages from HCV-infected individuals significantly decreased IFN-γ expression in CD8+ T-cells. Therefore, altered M1 macrophage differentiation in chronic HCV infection may contribute to observed CD8+ T-cell dysfunction. Understanding the immunological perturbations in chronic HCV infection will lead to the identification of therapeutic targets to restore immune function in HCV+ individuals, and aid in the mitigation of associated negative clinical outcomes.

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