Autoproliferation Contributes to Clonal Expansion and Changes In Cellular Topography In T Cell Large Granular Lymphocyte (LGL) Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1373-1373
Author(s):  
JianXiang Zou ◽  
Jeffrey S Painter ◽  
Fanqi Bai ◽  
Lubomir Sokol ◽  
Thomas P. Loughran ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Cd8 T Cell ◽  
Effector Memory ◽  
Ki67 Expression ◽  
Terminal Effector ◽  
Lgl Leukemia

Abstract Abstract 1373 Introduction: LGL leukemia is associated with cytopenias and expansion of clonally-derived mature cytotoxic CD8+ lymphocytes. The etiology of LGL leukemia is currently unknown, however, T cell activation, loss of lymph node homing receptor L-selectin (CD62L), and increased accumulation of T cells in the bone marrow may lead to suppressed blood cell production. The broad resistance to Fas (CD95) apoptotic signals has lead to the hypothesis that amplification of clonal cells occurs through apoptosis resistance. However, the proliferative history has not been carefully studied. To define possible mechanism of LGL leukemia expansion, T cell phenotype, proliferative history, and functional-related surface marker expression were analyzed. Methods: Peripheral blood mononuclear cells (PBMCs) were obtained from 16 LGL leukemia patients that met diagnostic criteria based on the presence of clonal aβ T cells and >300 cells/ml CD3+/CD57+ T cells in the peripheral blood. Samples were obtained from 10 age-matched healthy individuals from the Southwest Florida Blood Services for comparisons. Multi-analyte flow cytometry was conducted for expression of CD3, CD4/8, CD45RA, CD62L, CD27, CD28, CD25, CD127, IL15Ra, IL21a, CCR7 (all antibodies from BD Biosciences). The proliferative index was determined by Ki67 expression in fixed and permeabilized cells (BD Biosciences) and the proliferative history in vivo was assessed by T-cell-receptor excision circle (TREC) measurement using real-time quantitative PCR (qRT-PCR) in sorted CD4+ and CD8+ T cells. TRECs are episomal fragments generated during TCR gene rearrangements that fail to transfer to daughter cells and thus diminish with each population doubling that reflects the in vivo proliferative history. Results: Compared to healthy controls, significantly fewer CD8+ naïve cells (CD45RA+/CD62L+, 8.4 ± 10.8 vs 24.48 ± 11.99, p=0.003) and higher CD8+ terminal effector memory (TEM) T cells (CD45RA+/CD62L-, 67.74 ± 28.75 vs 39.33 ± 11.32, p=0.007) were observed in the peripheral blood. In contrast, the percentage of CD4+ naïve and memory cells (naïve, central memory, effector memory, and terminal effector memory based on CD45RA and CD62L expression) was similar in patients as compared to controls. The expression of CD27 (31.32 ± 34.64 vs 71.73 ± 20.63, p=0.003) and CD28 (31.38 ± 31.91 vs 70.02 ± 22.93, p=0.002) were lower in CD8+ T cell from patients with LGL leukemia and this reduction predominated within the TEM population (17.63±24.5 vs 70.98±22.5 for CD27, p<0.0001 and 13±20.5 vs 69.43± 21.59 for CD28, p<0.0001). Loss of these markers is consistent with prior antigen activation. There was no difference in CD25 (IL2Ra, p=0.2) expression on CD4+ or CD8+ T cells, but CD127 (IL7Ra, p=0.001), IL15Ra, and IL21Ra (p=0.15) were overexpressed in TEM CD8+ T cell in patients vs controls. All of these cytokine receptors belong to the IL2Rβg-common cytokine receptor superfamily that mediates homeostatic proliferation. In CD8+ T cells in patients, the IL-21Ra was also overexpressed in naïve, central and effector memory T cells. The topography of the expanded CD8+ T cell population was therefore consistent with overexpression of activation markers and proliferation-associated cytokine receptors. Therefore, we next analyzed Ki67 expression and TREC DNA copy number to quantify actively dividing cells and determine the proliferative history, respectively. We found that LGL leukemia patients have more actively dividing CD8+ TEM T cells compared to controls (3.2 ± 3.12 in patients vs 0.44 ± 0.44 in controls, p=0.001). Moreover, the TREC copy number in CD8+ T cells was statistically higher in healthy individuals after adjusting for age (177.54 ± 232 in patients vs 1015 ± 951 in controls, p=0.019). These results show that CD8+ cells in the peripheral compartment have undergone more population doublings in vivo compared to healthy donors. In contrast, the TREC copies in CD4+ T-cells were similar between LGL patients and controls (534.4 ± 644 in patients vs 348.78 ± 248.16 in controls, p>0.05) demonstrating selective cellular proliferation within the CD8 compartment. Conclusions: CD8+ T- cells are undergoing robust cellular activation, contraction in repertoire diversity, and enhanced endogenous proliferation in patients with LGL leukemia. Collectively, these results suggest that clonal expansion is at least partially mediated through autoproliferation in T-LGL leukemia. Disclosures: No relevant conflicts of interest to declare.

T Large Granular Lymphocyte (LGL) Leukemia Characterized by Expansion of Terminal CD3+/CD8+/CD62L−/CD45RA+ Effector Memory T Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4962-4962
Author(s):  
JianXiang Zou ◽  
Jeffrey S. Painter ◽  
Fanqi Bai ◽  
Thomas P. Loughran ◽  
P.K. Epling-Burnette
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Memory T Cells ◽  
Effector Memory ◽  
T Cell Proliferation ◽  
Normal Controls ◽  
Terminal Effector ◽  
Homeostatic Mechanisms ◽  
Lgl Leukemia

Abstract Background: Clonal proliferation by mature Large Granular Lymphocytes is associated with LGL leukemia. This expansion of CD3− NK cells or CD3+ T cells may be the result of chronic antigen stimulation by autoantigens or viral antigens. In association with T cell lymphoproliferation, approximately 45% of patients with LGL leukemia have severe neutropenia (absolute neutrophil count &lt;0.5×109/L) and 20% of patients have transfusion-dependent anemia. Homeostatic mechanisms normally modulate the generation of naïve and memory T cell pools and regulate the T cell repertoire; however, the pathways elicited during T memory differentiation, maintenance and expansion are not fully characterized. The goal of this work was to characterize the homeostatic mechanisms that regulate LGL leukemia. Methods: Peripheral blood mononuclear cells were isolated from patients with LGL leukemia and normal controls. We performed multiplex TCR-Vβ (CDR3) PCR on cells from 16 LGL patients to identify clonal T cell proliferation. The percentage of CD3+ T cells that expressed each of the TCR-Vβ families was determined in 20 healthy donors to establish the mean and standard deviation (S.D.) of the control population. Naïve and memory CD4 and CD8 T cell sub-populations were segregated by expression of CD45RA and CD62L expression by flow cytometry and T cell proliferation was assessed by Brdu incorporation in CD4+ and CD8+ T cells. Results: The absolute number of CD4+ T cells was reduced in LGL patients compared to normal donors and T cell clones were characterized by a CD8+ phenotype. By flow cytometry, expansion of a single Vβ clonal population occurred in 8 of 16 patients (50%), two clones were present in 4 of 16 patients (25%), and three clones in 4 of 16 patients (25%). The immunophenotype of TCR Vβ+ clonal T cells was CD8 positive, CD57 positive, CD28 negative, CD25 negative, and NKG2D (NKG2-family) positive and CD244 (2B4) positive. Three patients examined expressed Killer-Immunoglobulin-like (KIR) receptors. Further phenotype analysis showed that there were fewer than normal CD4+ naïve (CD4+/CD45RA+/CD62L+) T cells (23%±16 vs. 41%± 15, P=0.04 by a t test) in LGL patients. CD4+ T cells from patients had reduced proliferation in response to antigen stimulation. The reduction in CD4+ naïve T cells was associated with increased percentages of CD4+/CD45RA−/CD62L+ central memory T cells (P&lt;0.05). Reduced percentage of naive CD8+ T cells in detected in LGL leukemia patients. In addition, CD4+ central memory cells were also significantly reduced in patients. CD8+ T cells were primarily characterized by a CD45RA+/CD62L− terminal effector memory phenotype that was significantly increased compared to normal donors (mean 75% ± 13 in patients vs 30% ± 13 in normal controls, P&lt;0.0001). In the presence of a skewed repertoire and terminal effector memory cell accumulation, antigen-induced proliferation of CD8+ T cells in LGL did not differ from normal controls (13% ± 11 in patients vs. 9% ± 3 in normal controls, P=0.3). Conclusions: These results suggest that leukemic LGL represent the accumulation of CD8+ terminal effector memory cells with the capacity for increased proliferation. Our findings suggest that normal homeostatic signals are impaired in LGL leukemia that limits the terminal CD8 differentiation phase of an immune response.

A Comparison of Human CMVpp65-Specific Central Memory and Effector Memory CD8 T-Cells When Stimulated in-Vivo with IL-2 or IL-15/IL-15Rα Complex in a Murine Xenograft Model of Adoptive Cell Therapy

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4805-4805
Author(s):  
Tzu-Yun Kuo ◽  
Aisha Hasan ◽  
Richard J O'Reilly
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Adoptive Immunotherapy ◽  
Memory T Cells ◽  
Cd8 T Cell ◽  
Central Memory ◽  
Effector Memory ◽  
Cell Clones

Abstract Initial clinical trials of adoptive immunotherapy have shown that the efficacy of adoptively transferred T-cells in man is often limited by the failure of cultured T cells, particularly cloned CD8 T cells, to persist in vivo. These studies demonstrated that the transferred T cells induced only transient responses and that persistence of the transferred T-cell clonotypes correlated with disease regression. A previous study suggested that CMV virus-specific CD8 T cell clones derived from central memory T cells (TCM), but not effector memory T cells (TEM), persisted long-term in non-human primates. On the other hand, another study comparing TCM and TEM derived SIV virus specific CD8 T-cell clones that were adoptively transferred in non-human primates demonstrated limited persistence of both TCM and TEM derived transferred T cells, and failed to show any difference between the two cell types. Because of these conflicting data, we have reexamed the persistence of adoptively transferred viral antigen specific T-cells derived from TCM and TEM population. Accordingly, we developed a NOG mouse model for studying the ability of human CMVpp65-specific T cells derived from central memory and effector memory populations to migrate to and accumulate in human tumor xenografts expressing CMVpp65, to alter the growth of these tumors and to persist in the tumors. This model also allows us to test immunomodulating agents and their ability to enhance targeted T-cell accumulations, antitumor activity and persistence. We analyzed CMVpp65-specific CD8 T cells derived from TCM and TEM precursors in vitro and in vivo. To tract the T-cells in vivo, we transduced membrane-bound Gaussia luciferase into TCM and TEM populations and monitored T cell trafficking by in vivo bioluminescence. Contrary to expectation, our results initially showed no differences between TCM and TEM derived CMVpp65-specific T-cell in mice co-treated with IL-2 in the time to accumulation, ultimate level of accumulation, degree of CMVpp65+ tumor regression or T-cell persistence. However, in mice cotreated with IL-15/IL-15Rα complex, both TCM and TEM exhibited more sustained engraftment and more prolonged accumulation in both the targeted tumor and in the marrow. In mice treated with IL-15/IL-15Rα, TCM and TEM derived T cells showed a similar effector memory phenotype and a similar level of regression of tumor growth. Thus, adoptive transfer of CMVpp65 specific TCM or TEM when combined with IL-15/IL-15Rα complex may support better persistence of antigen-specific T-cells following adoptive immunotherapy. Studies comparing IL-15/IL-15Rα complex with IL-15 alone are in progress. Disclosures No relevant conflicts of interest to declare.

scholarly journals Longitudinal Changes in Cd4+, Cd8+ T Cell Phenotype and Activation Marker Expression Following Antiretroviral Therapy Initiation among Patients with Cryptococcal Meningitis

2019 ◽  
Vol 5 (3) ◽  
pp. 63
Author(s):  
Alice Bayiyana ◽  
Samuel Okurut ◽  
Rose Nabatanzi ◽  
Godfrey Zziwa ◽  
David R. Boulware ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antiretroviral Therapy ◽  
Cell Surface ◽  
Cd8 T Cells ◽  
Cryptococcal Meningitis ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
Effector Memory ◽  
Memory Subset

Despite improvement in the prognosis of HIV/AIDS (human immunodeficiency virus/acquired immune deficiency syndrome) patients on antiretroviral therapy (ART), cryptococcal meningitis (CM) still causes 10–15% mortality among HIV-infected patients. The immunological impact of ART on the CD4+ and CD8+ T cell repertoire during cryptococcal co-infection is unclear. We determined longitudinal phenotypic changes in T cell subsets among patients with CM after they initiated ART. We hypothesized that ART alters the clonotypic phenotype and structural composition of CD4+ and CD8+ T cells during CM co-infection. For this substudy, peripheral blood mononuclear cells (PBMC) were isolated at four time points from CM patients following ART initiation during the parent study (ClinicalTrials.gov number, NCT01075152). Phenotypic characterization of CD4+ and CD8+ T cells was done using T cell surface marker monoclonal antibodies by flow cytometry. There was variation in the expression of immunophenotypic markers defining central memory (CD27+CD45R0+), effector memory (CD45R0+CD27–), immune activation (CD38+ and Human Leucocyte Antigen DR (HLA-DR+), and exhaustion (Programmed cell death protein one (PD-1) in the CD4+ T cell subset. In comparison to the CD4+ T cell population, the CD8+ central memory subset declined gradually with minimal increase in the effector memory subset. Both CD4+ and CD8+ T cell immune exhaustion and activation markers remained elevated over 12 weeks. The relative surge and decline in the expression of T cell surface markers outlines a variation in the differentiation of CD4+ T cells during ART treatment during CM co-infection.

IL-8 responsiveness defines a subset of CD8 T cells poised to kill

Blood ◽  
2004 ◽  
Vol 104 (12) ◽  
pp. 3463-3471 ◽  
Author(s):  
Christoph Hess ◽  
Terry K. Means ◽  
Patrick Autissier ◽  
Tonia Woodberry ◽  
Marcus Altfeld ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chemokine Receptor ◽  
Cd8 T Cells ◽  
Molecular Mechanisms ◽  
Cell Subset ◽  
Cd8 T Cell ◽  
Effector Memory ◽  
Immune System Activation ◽  
Hiv 1

CD8 T cells play a key role in host defense against intracellular pathogens. Efficient migration of these cells into sites of infection is therefore intimately linked to their effector function. The molecular mechanisms that control CD8 T-cell trafficking into sites of infection and inflammation are not well understood, but the chemokine/chemokine receptor system is thought to orchestrate this process. Here we systematically examined the chemokine receptor profile expressed on human CD8 T cells. Surprisingly, we found that CXC chemokine receptor 1 (CXCR1), the predominant neutrophil chemokine receptor, defined a novel interleukin-8/CXC ligand 8 (IL-8/CXCL8)–responsive CD8 T-cell subset that was enriched in perforin, granzyme B, and interferon-γ (IFNγ), and had high cytotoxic potential. CXCR1 expression was down-regulated by antigen stimulation both in vitro and in vivo, suggesting antigen-dependent shaping of the migratory characteristics of CD8 T cells. On virus-specific CD8 T cells from persons with a history of Epstein-Barr virus (EBV) and influenza infection, CXCR1 expression was restricted to terminally differentiated effector memory cells. In HIV-1 infection, CXCR1-expressing HIV-1–specific CD8 T cells were present only in persons who were able to control HIV-1 replication during structured treatment interruptions. Thus, CXCR1 identifies a subset of CD8 T cells poised for immediate cytotoxicity and early recruitment into sites of innate immune system activation.

scholarly journals DNAM-1 promotes activation of cytotoxic lymphocytes by nonprofessional antigen-presenting cells and tumors

2008 ◽  
Vol 205 (13) ◽  
pp. 2965-2973 ◽  
Author(s):  
Susan Gilfillan ◽  
Christopher J. Chan ◽  
Marina Cella ◽  
Nicole M. Haynes ◽  
Aaron S. Rapaport ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Adhesion Molecules ◽  
Cd8 T Cells ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Antigen Presenting

Natural killer (NK) cells and CD8 T cells require adhesion molecules for migration, activation, expansion, differentiation, and effector functions. DNAX accessory molecule 1 (DNAM-1), an adhesion molecule belonging to the immunoglobulin superfamily, promotes many of these functions in vitro. However, because NK cells and CD8 T cells express multiple adhesion molecules, it is unclear whether DNAM-1 has a unique function or is effectively redundant in vivo. To address this question, we generated mice lacking DNAM-1 and evaluated DNAM-1–deficient CD8 T cell and NK cell function in vitro and in vivo. Our results demonstrate that CD8 T cells require DNAM-1 for co-stimulation when recognizing antigen presented by nonprofessional antigen-presenting cells; in contrast, DNAM-1 is dispensable when dendritic cells present the antigen. Similarly, NK cells require DNAM-1 for the elimination of tumor cells that are comparatively resistant to NK cell–mediated cytotoxicity caused by the paucity of other NK cell–activating ligands. We conclude that DNAM-1 serves to extend the range of target cells that can activate CD8 T cell and NK cells and, hence, may be essential for immunosurveillance against tumors and/or viruses that evade recognition by other activating or accessory molecules.

scholarly journals Mitochondrial Dysfunction Associates With Acute T Lymphocytopenia and Impaired Functionality in COVID-19 Patients

2022 ◽  
Vol 12 ◽  
Author(s):  
Yufei Mo ◽  
Kelvin Kai-Wang To ◽  
Runhong Zhou ◽  
Li Liu ◽  
Tianyu Cao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mitochondrial Dysfunction ◽  
Cd8 T Cells ◽  
Functional Impairment ◽  
Cell Loss ◽  
Cd8 T Cell ◽  
Underlying Mechanism ◽  
T Cell Subsets ◽  
Effector Memory

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection results in rapid T lymphocytopenia and functional impairment of T cells. The underlying mechanism, however, remains incompletely understood. In this study, we focused on characterizing the phenotype and kinetics of T-cell subsets with mitochondrial dysfunction (MD) by multicolor flow cytometry and investigating the association between MD and T-cell functionality. While 73.9% of study subjects displayed clinical lymphocytopenia upon hospital admission, a significant reduction of CD4 or CD8 T-cell frequency was found in all asymptomatic, symptomatic, and convalescent cases. CD4 and CD8 T cells with increased MD were found in both asymptomatic and symptomatic patients within the first week of symptom onset. Lower proportion of memory CD8 T cell with MD was found in severe patients than in mild ones at the stage of disease progression. Critically, the frequency of T cells with MD in symptomatic patients was preferentially associated with CD4 T-cell loss and CD8 T-cell hyperactivation, respectively. Patients bearing effector memory CD4 and CD8 T cells with the phenotype of high MD exhibited poorer T-cell responses upon either phorbol 12-myristate-13-acetate (PMA)/ionomycin or SARS-CoV-2 peptide stimulation than those with low MD. Our findings demonstrated an MD-associated mechanism underlying SARS-CoV-2-induced T lymphocytopenia and functional impairment during the acute phase of infection.

scholarly journals Adrenergic signaling controls early transcriptional programs during CD8+ T cell responses to viral infection

2021 ◽  
Author(s):  
Leonardo Estrada ◽  
Didem Agac Cobanoglu ◽  
Aaron Wise ◽  
Robert Maples ◽  
Murat Can Cobanoglu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Receptor Activation ◽  
Cell Development ◽  
Primary Response ◽  
Cell Responses

Viral infections drive the expansion and differentiation of responding CD8+ T cells into variegated populations of cytolytic effector and memory cells. While pro-inflammatory cytokines and cell surface immune receptors play a key role in guiding T cell responses to infection, T cells are also markedly influenced by neurotransmitters. Norepinephrine is a key sympathetic neurotransmitter, which acts to suppress CD8 + T cell cytokine secretion and lytic activity by signaling through the beta2-adrenergic receptor (ADRB2). Although ADRB2 signaling is considered generally immunosuppressive, its role in regulating differentiation of effector T cells in response to infection has not been investigated. Using an adoptive transfer approach, we compared the expansion and differentiation of wild type (WT) to Adrb2-/- CD8 + T cells throughout the primary response to vesicular stomatitis virus (VSV) infection in vivo. We measured the dynamic changes in transcriptome profiles of antigen-specific CD8 + T cells as they responded to VSV. Within the first 7 days of infection, WT cells out-paced the expansion of Adrb2-/- cells, which correlated with reduced expression of IL-2 and the IL-2Ralpha; in the absence of ADRB2. RNASeq analysis identified over 300 differentially expressed genes that were both temporally regulated following infection and selectively regulated in WT vs Adrb2-/- cells. These genes contributed to major transcriptional pathways including cytokine receptor activation, signaling in cancer, immune deficiency, and neurotransmitter pathways. By parsing genes within groups that were either induced or repressed over time in response to infection, we identified three main branches of genes that were differentially regulated by the ADRB2. These gene sets were predicted to be regulated by specific transcription factors involved in effector T cell development, such as Tbx21 and Eomes. Collectively, these data demonstrate a significant role for ADRB2 signaling in regulating key transcriptional pathways during CD8 + T cells responses to infection that may dramatically impact their functional capabilities and downstream memory cell development.

MicroRNA-17∼92 regulates effector and memory CD8 T-cell fates by modulating proliferation in response to infections

Blood ◽  
2013 ◽  
Vol 121 (22) ◽  
pp. 4473-4483 ◽  
Author(s):  
Arif A. Khan ◽  
Laura A. Penny ◽  
Yevgeniy Yuzefpolskiy ◽  
Surojit Sarkar ◽  
Vandana Kalia
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Mtor Signaling ◽  
Cell Fates ◽  
Key Points ◽  
Memory Cd8 T Cell ◽  
Terminal Effector

Key Points miR-17∼92 promotes proliferation and terminal effector differentiation in CD8 T-cells by upregulating PI3K-AKT-mTOR signaling.

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 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.

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