A Loss of Function of the Mitochondrial Branched-Chain Aminotransferase (BCATm) Leads to Increased Glycolytic and Oxidative Metabolism in Activated CD4+ T Cells

Abstract Objectives T cells use the amino acid leucine to respond to their increased biosynthetic demands during activation. However, once inside T cells, leucine is subjected to degradation, which is initiated by the mitochondrial branched-chain aminotransferase (BCATm) that catalyzes the reversible transamination of leucine. We hypothesized that if BCATm is absent from T cells, this would provide more intracellular leucine to stimulate T cell metabolism. Methods To explore the dependence of T cells on BCATm function, we isolated CD4+ T cells from spleens of wild type (WT) and BCATm global knockout (KO) mice, and after cell activation with anti-CD3 and anti-CD28 for 24 h, we measured leucine transamination, glycolysis, mitochondrial respiration and ATP synthesis, the activity of the mammalian target of rapamycin (mTOR) pathway, and the release of IFN-γ. Results The global deletion of BCATm resulted in a 1.8-fold reduction in leucine transamination and a 1.2-fold increase in the intracellular leucine concentrations in activated CD4+ T cells from BCATmKO mice. These T cells demonstrated 4.0– and 5.0-fold increases in glycolysis and glycolytic capacity, along with 1.8– and 2-0-fold increases in the maximal respiration and spare respiratory capacity when compared to WT T cells after 24 h of activation. In addition, mTOR signaling was more active in BCATmKO T cells and their IFN-γ release was increased by 2.1-fold relative to WT T cells. Conclusions The results suggested that leucine catabolism at the BCATm step negatively affects T cell metabolism by limiting glycolytic intermediates for biosynthetic needs and mitochondrial respiration for energy. Thus, leucine catabolism is regarded as a metabolic checkpoint of T cells that may prove useful for therapeutic purposes. Funding Sources Des Moines University, (IOER-112-3705 to EAS), the National Institute of Health (DK 34,738 to SMH).

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Immune profiling of Mycobacterium tuberculosis-specific T cells in recent and remote infection

10.1101/2020.11.13.20230946 ◽

2020 ◽

Author(s):

Cheleka A.M. Mpande ◽

Virginie Rozot ◽

Boitumelo Mosito ◽

Munyaradzi Musvosvi ◽

One B Dintwe ◽

...

Keyword(s):

T Cells ◽

Mycobacterium Tuberculosis ◽

T Cell ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Differentially Expressed ◽

Cd4 T Cell ◽

Remote Infection ◽

Ifn Γ

AbstractBackgroundRecent Mycobacterium tuberculosis (M.tb) infection is associated with a higher risk of progression to tuberculosis disease, compared to persistent infection after remote exposure. However, current immunodiagnostic tools fail to distinguish between recent and remote infection. We aimed to characterise the immunobiology associated with acquisition of M.tb infection and identify a biomarker that can distinguish recent from remote infection.MethodsHealthy South African adolescents were serially tested with QuantiFERON-TB Gold to define recent (QuantiFERON-TB conversion <6 months) and persistent (QuantiFERON-TB+ for >1.5 year) infection. We characterized M.tb-specific CD4 T cell functional (IFN-γ, TNF, IL-2, CD107, CD154), memory (CD45RA, CCR7, CD27, KLRG-1) and activation (HLA-DR) profiles by flow cytometry after CFP-10/ESAT-6 peptide pool or M.tb lysate stimulation. We then assessed the diagnostic performance of immune profiles that were differentially expressed between individuals with recent or persistent QuantiFERON-TB+.FindingsCFP-10/ESAT-6-specific CD4 T cell activation but not functional or memory phenotypes distinguished between individuals with recent and persistent QuantiFERON-TB+. In response to M.tb lysate, recent QuantiFERON-TB+ individuals had lower proportions of highly differentiated IFN-γ+TNF+ CD4 T cells expressing a KLRG-1+ effector phenotype and higher proportions of early differentiated IFN-γ-TNF+IL-2+ and activated CD4 T cells compared to persistent QuantiFERON-TB+ individuals. Among all differentially expressed T cell features CFP-10/ESAT-6-specific CD4 T cell activation was the best performing diagnostic biomarker of recent infection.InterpretationRecent M.tb infection is associated with highly activated and moderately differentiated functional M.tb-specific T cell subsets, that can be used as biomarkers to distinguish between recent and remote infection.

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

Infection and Immunity ◽

10.1128/iai.00024-07 ◽

2007 ◽

Vol 75 (5) ◽

pp. 2244-2252 ◽

Cited By ~ 26

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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CD4 T Cell Cytokine Differentiation: The B Cell Activation Molecule, OX40 Ligand, Instructs CD4 T Cells to Express Interleukin 4 and Upregulates Expression of the Chemokine Receptor, Blr-1

Journal of Experimental Medicine ◽

10.1084/jem.188.2.297 ◽

1998 ◽

Vol 188 (2) ◽

pp. 297-304 ◽

Cited By ~ 252

Author(s):

Sarah Flynn ◽

Kai-Michael Toellner ◽

Chandra Raykundalia ◽

Margaret Goodall ◽

Peter Lane

Keyword(s):

T Cells ◽

T Cell ◽

Chemokine Receptor ◽

Cd4 T Cells ◽

Cell Activation ◽

Interleukin 4 ◽

Th2 Cells ◽

Ox40 Ligand ◽

Ifn Γ

This report investigates the role of OX40 ligand (OX40L) and its receptor, OX40, expressed on activated B and T cells, respectively, in promoting the differentiation of T helper type 2 (Th2) CD4 T cells. These molecules are expressed in vivo by day 2 after priming with T cell– dependent antigens. Their expression coincides with the appearance of immunoglobulin (Ig)G switch transcripts and mRNA for interleukin (IL)-4 and interferon (IFN)-γ, suggesting that this molecular interaction plays a role in early cognate interactions between B and T cells. In vitro, we report that costimulation of naive, CD62Lhigh CD4 T cells through OX40 promotes IL-4 expression and upregulates mRNA for the chemokine receptor, blr-1, whose ligand is expressed in B follicles and attracts lymphocytes to this location. Furthermore, T cell stimulation through OX40 inhibits IFN-γ expression in both CD8 T cells and IL-12–stimulated CD4 T cells. Although this signal initiates IL-4 expression, IL-4 itself is strongly synergistic. Our data suggest that OX40L on antigen-activated B cells instructs naive T cells to differentiate into Th2 cells and migrate into B follicles, where T cell–dependent germinal centers develop.

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Blocking ICOS-B7h Signal Can Inhibit the Function of Allogene T Lymphocytes and Decrease the Incidence and Severity of Acute Graft Versus Host Disease in Mouse Model

Blood ◽

10.1182/blood.v112.11.4606.4606 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4606-4606

Author(s):

Xiaochen Bao ◽

Ningxia Song ◽

Bin Wang ◽

Jianmin Wang

Keyword(s):

T Cells ◽

T Cell ◽

Fusion Protein ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Recipient Mouse ◽

T Helper ◽

Graft Versus Host ◽

Ifn Γ

Abstract ICOS, a CD28 family member expressed on activated T cells, plays important roles in T cell activation and effector function. Here we report our results of biological activity of ICOS signal on allogeneic T lymphocytes and its effect on acute graft-versus-host disease in mouse model by blocking ICOS-B7h signal with ICOS-Ig fusion protein. Human ICOSIg fusion protein was harvested and purified from supernatant of CHO cells transfected with pSecTag2/Hygro A-ICOS-Ig in our lab. Spleen CD4+ cells from C57BL/6 mouse were stimulated with dendritic cells from BALB/C mouse, with different doses of ICOS-Ig or human-Ig (h-Ig) as controls. Allogeneic aGVHD model was established with lethally irradiated BALB/c recipients receiving allogeneic BM and spleen T cells from C57BL/6 mouse with 100ug ICOS-Ig or h-Ig intropenetoneally 4 times at day 0, day +2, +4 and +6 of transplantation. RESULTS: ICOS-Ig (10ug/mL) significantly inhibited proliferation of CD4+T cells ( P<0.01), decreased the level of TNF-α and elevated level of IL-4 in the supernatants of CD4+ T cells in response to allogeneic mature DCs but had no effect on IFN-γ production; ICOS-Ig blockade elevated apoptosis of splenic CD4+ T cells while had no effect on T cell activation (CD25 expression). ICOS-Ig blockade significantly attenuated the lethal GVHD that occurred in control recipient mice. The average survival time was 13.25±5.87 days for mice in h-Ig group, while 21.42±3.02 days for animals in ICOS-Ig group(p=0.0217). Pathologic evaluation revealed that the liver and intestine of animals in ICOS-Ig group has less lymphocyte infiltration and less architectural disruption than those in control h-Ig group; In vivo, ICOS-Ig had no effect on allogeneic T cells division (h-Ig :98.40±1.32, ICOS-Ig: 97.69±2.19 by FACS analysis of CFSE labeled lymphocyte at day 3 of transplantation) and no effect on the proportion of CD4+/CD8+ (h-Ig: 26.35±0.07, ICOS-Ig: 22.12±0.21), but increased apoptosis of allogeneic CD8+ T cells in GVHD model by FACS analysis of Annexin-V staining lymphocytes at day 10 of transplantation (h-Ig: 20.44±3.83, ICOS-Ig: 22.87±6.94 in CD4+ T cells; h-Ig: 18.73±7.43, ICOS-Ig: 24.03±5.4 in CD8+ T cells). Spleen T cells from mice after transplantation were stimulated by ConA ex vivo, ICOS-Ig group proliferated less than control h-Ig group through cell counting with CCK-8 (h-Ig: 0.86±0.04,ICOS-Ig: 0.69±0.12,P<0.05). (4) ICOS-Ig significantly reduced the secretion of IFN-γ and elevated IL-4 in the serum of recipient mouse. The IFN-γ (pg/mL) detected were 562.27±49.97 in h-Ig group, 49.79±2.81 in ICOS-Ig group; and the IL-4 (pg/mL) detected were 38.819±27.56 in h-Ig group,456.03±69.63 in ICOS-Ig group. (p<0.05). (5)ICOS-Ig significantly reduced the secretion of T-bet and elevated GATA-3 in the spleens of recipient mouse. The T-bet/GATA-3 detected were 1.87±0.65 in h-Ig group, 0.56±0.03 in ICOS-Ig (p=0.03). CONCLUSION: The ICOS-Ig fusion protein had bioactivity of inhibition of T cell proliferation and alternated the polarization of T helper cells; It promoted the apoptosis of allo-reactive T cells from donor animals but had no effect on the activation of allo-reactive CD4+T cells; ICOS-Ig blockade can prevent aGVHD through attenuating the function of the allo-reactive T cells, elevating apoptosis of allo-reactive T cells and alternating the polarization of T helper cells.

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Abstract 621: Homocysteine Activates T Cells by Enhancing Endoplasmic Reticulum-mitochondria Coupling and Increasing Mitochondrial Respiration

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.35.suppl_1.621 ◽

2015 ◽

Vol 35 (suppl_1) ◽

Author(s):

Juan Feng ◽

Xian Wang

Keyword(s):

Cell Proliferation ◽

T Cells ◽

T Cell ◽

T Cell Activation ◽

Mitochondrial Respiration ◽

Cell Activation ◽

Metabolic Reprogramming ◽

T Cell Proliferation ◽

Mitochondrial Ros ◽

Ifn Γ

Hyperhomocysteinemia (HHcy) accelerates atherosclerosis by affecting the immuno-inflammatory response, increasing proliferation and stimulating cytokine secretion in T cells. However, whether homocysteine (Hcy) activation of T cells is associated with metabolic reprogramming is unclear. Here, we showed that Hcy (50 μM, 24 hr)-stimulated splenic T-cell proliferation in mice was accompanied by increased levels of mitochondrial reactive oxygen species (ROS) by 23.25±2.27%, calcium overload, increased mitochondrial mass by 24.29±7.97% and increased respiration. Inhibiting mitochondrial ROS levels and calcium signals or blocking mitochondrial respiration largely blunted Hcy-induced T-cell activation. Hcy also enhanced endoplasmic reticulum (ER) stress in T cells. Inhibiting ER stress with 4-phenylbutyric acid or mitochondrial respiration by rotenone blocked Hcy-induced T-cell proliferation and interferon-γ (IFN-γ) secretion. Mechanistically, Hcy treatment increased ER-mitochondria coupling as revealed by structured illumination microscopy and elevated expression of tethering proteins MFN2, Gpx7, and ERP44. Uncoupling ER and mitochondria by the microtubule inhibitor nocodazole attenuated Hcy-stimulated mitochondrial ROS production, calcium overload, mitochondrial membrane potential, IFN-γ secretion and T-cell proliferation; thus, juxtaposition of ER and mitochondria is required for Hcy-promoted mitochondrial function and T-cell activation. In conclusion, Hcy promotes T-cell proliferation and IFN-γ secretion by inducing metabolic reprogramming via regulating ER-mitochondrial coupling. Our results highlight the importance of metabolic regulation in T-cell activation and shed new light on understanding the pathogenesis of HHcy-accelerated atherosclerosis.

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SUN-649 Metabolic and Functional Regulation of T Cells by Insulin and Insulin like Growth Factor 1

Journal of the Endocrine Society ◽

10.1210/jendso/bvaa046.1069 ◽

2020 ◽

Vol 4 (Supplement_1) ◽

Author(s):

Kaitlin Kiernan ◽

Nancie J MacIver

Keyword(s):

T Cells ◽

T Cell ◽

Growth Factor ◽

Glucose Uptake ◽

Cd4 T Cells ◽

Cell Metabolism ◽

Cell Subset ◽

Cd4 T Cell ◽

Ifn Γ ◽

And Function

Abstract Obesity leads to altered immunity characterized by increased risk of autoimmunity, poor response to infection, and impaired vaccine response. T cells play an important role in this obesity-associated immune response; however, the mechanisms by which T cells are altered in obesity remain unknown. Our goal is to identify nutritionally regulated hormones and cytokines that link whole body nutrition and immunity, and to understand the mechanisms by which such factors can alter T cell response in obesity. To that end, we have identified the hormones insulin and insulin-like growth factor-1 (IGF-1) as potential links between nutritional status and T cell metabolism and function. Insulin is secreted from pancreatic beta cells in response to increasing blood glucose levels, and circulating insulin levels are elevated in obesity due to insulin resistance in metabolic tissues. IGF-1 levels are influenced by protein intake and nutrition status, and free (bioactive) levels of IGF-1 are elevated in obesity. To study the role of insulin and IGF-1 on T cell function and metabolism, we treated activated CD4 T cells with physiologic levels of insulin or IGF-1 in vitro for 24 hours. Treatment of CD4 T cells with insulin or IGF-1 increased glucose uptake, glycolytic metabolism, and mitochondrial metabolism while altering inflammatory cytokine production. In particular, both insulin and IGF-1 decreased IFN-γ production, whereas IGF-1 specifically increased IL-17 production from both bulk activated CD4 T cells and T cells skewed toward a T helper 17 (Th17) phenotype. Using a T cell-specific insulin receptor (IR) conditional knockout mouse, we found that loss of IR signaling decreased glucose uptake and mitochondrial metabolism and increased IFN-γ production by activated T cells. Moreover, IR appears to be required for both insulin and IGF-1 effects on T cells. Lastly, we investigated the CD4 T cell subset-specific expression of both IR and IGF-1 receptor (IGF-1R). We found that each CD4 T cell subset had its own unique expression of both IR and IGF-1R; however Th17 cells had a striking increase in IGF-1R expression compared to the other T cell subsets, indicating a specific role for IGF-1 in promoting inflammation. These findings underscore the ability of the nutritionally-regulated hormones insulin and IGF-1 to modulate CD4 T cell metabolism and function and thereby alter T cell immunity, which has direct clinical relevance in both normal physiology and in obesity.

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Intestinal epithelial cells from inflammatory bowel disease patients preferentially stimulate CD4+ T cells to proliferate and secrete interferon-γ

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00294.2006 ◽

2007 ◽

Vol 292 (6) ◽

pp. G1630-G1640 ◽

Cited By ~ 46

Author(s):

Iris Dotan ◽

Matthieu Allez ◽

Atsushi Nakazawa ◽

Jens Brimnes ◽

Micoll Schulder-Katz ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Cd4 T Cell ◽

T Cell Proliferation ◽

Intestinal Epithelial ◽

Inflammatory Bowel ◽

Ifn Γ

Previous studies have suggested that intestinal epithelial cells (IECs) have the capacity to function as nonprofessional antigen presenting cells that in the normal state preferentially activate CD8+ T cells. However, under pathological conditions, such as those found in inflammatory bowel disease (IBD), persistent activation of CD4+ T cells is seen. The aim of this study was to determine whether the IBD IECs contribute to CD4+ T cell activation. Freshly isolated human IECs were obtained from surgical specimens of patients with or without IBD and cocultured with autologous or allogeneic peripheral blood T lymphocytes. Cocultures of normal T cells and IECs derived from IBD patients resulted in the preferential activation of CD4+ T cell proliferation that was associated with significant IFN-γ, but not IL-2, secretion. Cytokine secretion and CD4+ T cell proliferation was inhibited by pretreatment of the IBD IECs with the anti-DR MAb L243. In contrast, normal IECs stimulated the proliferation and cytokine secretion by CD4+ T cells to a significantly lesser degree than IBD IECs. Furthermore, blockade of human leukocyte antigen-DR had a lesser effect in the normal IEC-CD4+ T cell cocultures. We conclude that IECs can contribute to the ongoing CD4+ T cell activation seen in IBD. We suggest that the apparent differences between the secreted levels of IFN-γ indicate that it may play a dual role in intestinal homeostasis, in which low levels contribute to physiological inflammation whereas higher levels are associated with an uncontrolled inflammatory state.

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The Impact of Exercise Serum on Selected Parameters of CD4+ T Cell Metabolism

Immuno ◽

10.3390/immuno1030008 ◽

2021 ◽

Vol 1 (3) ◽

pp. 119-131

Author(s):

Jana Palmowski ◽

Kristina Gebhardt ◽

Thomas Reichel ◽

Torsten Frech ◽

Robert Ringseis ◽

...

Keyword(s):

T Cells ◽

Oxygen Consumption ◽

T Cell ◽

Real Time ◽

Cd4 T Cells ◽

Cell Metabolism ◽

Cd4 T Cell ◽

Autologous Serum ◽

Cell Phenotype ◽

The Impact

CD4+ T cells are sensitive to peripheral changes of cytokine levels and metabolic substrates such as glucose and lactate. This study aimed to analyze whether factors released after exercise alter parameters of human T cell metabolism, specifically glycolysis and oxidative phosphorylation. We used primary human CD4+ T cells activated in the presence of autologous serum, which was collected before (CO) and after a 30-min exercise intervention (EX). In the course of activation, cells and supernatants were analyzed for cell viability and diameter, real-time oxygen consumption by using PreSens Technology, mRNA expression of glycolytic enzymes and complexes of the electron transport chain by real-time PCR, glucose, and lactate levels in supernatants, and in vitro differentiation by flow cytometry. EX did not alter T cell phenotype, viability, or on-blast formation. Similarly, no difference between CO and EX were found for CD4+ T cell activation and cellular oxygen consumption. In contrast, higher levels of glucose were found after 48 h activation in EX conditions. T cells activated in autologous exercise serum expressed lower HK1 mRNA and higher IFN-γ receptor 1. We suggest that the exercise protocol used was not sufficient to destabilize the immune metabolism of T cells. Therefore, more intense and prolonged exercise should be used in future studies.

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Probiotic supplementation reduces inflammatory profiles but does not prevent oral immune perturbations during SIV infection

Scientific Reports ◽

10.1038/s41598-021-93918-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Rhianna Jones ◽

Kyle Kroll ◽

Courtney Broedlow ◽

Luca Schifanella ◽

Scott Smith ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cd4 T Cells ◽

Cell Activation ◽

Rhesus Macaques ◽

Oral Microbiome ◽

Probiotic Supplementation ◽

Siv Infection ◽

Anti Inflammatory

AbstractHIV/SIV infections lead to massive loss of mucosal CD4 + T cells and breakdown of the epithelial mucosa resulting in severe microbial dysbiosis and chronic immune activation that ultimately drive disease progression. Moreover, disruption of one of the most understudied mucosal environments, the oral cavity, during HIV-induced immunosuppression results in significant microbial and neoplastic co-morbidities and contributes to and predicts distal disease complications. In this study we evaluated the effects of oral probiotic supplementation (PBX), which can stimulate and augment inflammatory or anti-inflammatory pathways, on early SIV infection of rhesus macaques. Our study revealed that similar to the GI mucosae, oral CD4 + T cells were rapidly depleted, and as one of the first comprehensive analyses of the oral microflora in SIV infection, we also observed significant modulation among two genera, Porphyromonas and Actinobacillus, early after infection. Interestingly, although PBX therapy did not substantially protect against oral dysbiosis or ameliorate cell loss, it did somewhat dampen inflammation and T cell activation. Collectively, these data provide one of the most comprehensive evaluations of SIV-induced changes in oral microbiome and CD4 + T cell populations, and also suggest that oral PBX may have some anti-inflammatory properties in lentivirus infections.

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CCL19 enhances CD8+ T-cell responses and accelerates HBV clearance

Journal of Gastroenterology ◽

10.1007/s00535-021-01799-8 ◽

2021 ◽

Author(s):

Yan Yan ◽

Wei Zhao ◽

Wei Liu ◽

Yan Li ◽

Xu Wang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Crucial Role ◽

Cell Activation ◽

Hbv Infection ◽

Host Immune System ◽

Tnf Α ◽

Ifn Γ ◽

High Level

Abstract Background Chemokine (C–C motif) ligand 19 (CCL19) is a leukocyte chemoattractant that plays a crucial role in cell trafficking and leukocyte activation. Dysfunctional CD8+ T cells play a crucial role in persistent HBV infection. However, whether HBV can be cleared by CCL19-activated immunity remains unclear. Methods We assessed the effects of CCL19 on the activation of PBMCs in patients with HBV infection. We also examined how CCL19 influences HBV clearance and modulates HBV-responsive T cells in a mouse model of chronic hepatitis B (CHB). In addition, C–C chemokine-receptor type 7 (CCR7) knockdown mice were used to elucidate the underlying mechanism of CCL19/CCR7 axis-induced immune activation. Results From in vitro experiments, we found that CCL19 enhanced the frequencies of Ag-responsive IFN-γ+ CD8+ T cells from patients by approximately twofold, while CCR7 knockdown (LV-shCCR7) and LY294002 partially suppressed IFN-γ secretion. In mice, CCL19 overexpression led to rapid clearance of intrahepatic HBV likely through increased intrahepatic CD8+ T-cell proportion, decreased frequency of PD-1+ CD8+ T cells in blood and compromised suppression of hepatic APCs, with lymphocytes producing a significantly high level of Ag-responsive TNF-α and IFN-γ from CD8+ T cells. In both CCL19 over expressing and CCR7 knockdown (AAV-shCCR7) CHB mice, the frequency of CD8+ T-cell activation-induced cell death (AICD) increased, and a high level of Ag-responsive TNF-α and low levels of CD8+ regulatory T (Treg) cells were observed. Conclusions Findings in this study provide insights into how CCL19/CCR7 axis modulates the host immune system, which may promote the development of immunotherapeutic strategies for HBV treatment by overcoming T-cell tolerance.

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