scholarly journals Low Levels of T Cell Exhaustion in Tuberculous Lung Granulomas

2018 ◽  
Vol 86 (9) ◽  
Author(s):  
Eileen A. Wong ◽  
Louis Joslyn ◽  
Nicole L. Grant ◽  
Edwin Klein ◽  
Philana Ling Lin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cells ◽  
Cell Function ◽  
Cell Activity ◽  
Intrinsic Property ◽  
T Cell Exhaustion ◽  
Inhibitory Receptors ◽  
Content Type ◽  
Cell Exhaustion

ABSTRACTThe hallmarks of pulmonaryMycobacterium tuberculosisinfection are lung granulomas. These organized structures are composed of host immune cells whose purpose is to contain or clear infection, creating a complex hub of immune and bacterial cell activity, as well as limiting pathology in the lungs. Yet, given cellular activity and the potential for frequent interactions between host immune cells andM. tuberculosis-infected cells, we observed a surprisingly low quantity of cytokine-producing T cells (<10% of granuloma T cells) in our recent study ofM. tuberculosisinfection within nonhuman primate (NHP) granulomas. Various mechanisms could limit T cell function, and one hypothesis is T cell exhaustion. T cell exhaustion is proposed to result from continual antigen stimulation, inducing them to enter a state characterized by low cytokine production, low proliferation, and expression of a series of inhibitory receptors, the most common being PD-1, LAG-3, and CTLA-4. In this work, we characterized the expression of inhibitory receptors on T cells and the functionality of these cells in tuberculosis (TB) lung granulomas. We then used these experimental data to calibrate and inform an agent-based computational model that captures environmental, cellular, and bacterial dynamics within granulomas in lungs duringM. tuberculosisinfection. Together, the results of the modeling and the experimental work suggest that T cell exhaustion alone is not responsible for the low quantity ofM. tuberculosis-responsive T cells observed within TB granulomas and that the lack of exhaustion is likely an intrinsic property of granuloma structure.

scholarly journals Metabolic Reprogramming and Intervention During T Cell Exhaustion

2021 ◽  
Author(s):  
Fei Li ◽  
Huiling Liu ◽  
Dan Zhang ◽  
Bingdong Zhu
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Cell Metabolism ◽  
T Cell Exhaustion ◽  
Naive T Cells ◽  
Cell Exhaustion ◽  
Naïve T Cells ◽  
T Cell Function ◽  
Prevention And Treatment

Recent studies have shown that T cell metabolism has become a key regulator of T cell function and even can determine T cell function at last. Naïve T cells use fatty acid oxidation (FAO) to meet their energetic demands. Effector T cells mainly rely on aerobic glycolysis to supply energy and synthesize intermediate products. Similar to naïve T cells, memory T cells primarily utilize FAO for energy. Exhausted T cells, which can be induced by continuous activation of T cells upon persistently chronic infections such as tuberculosis, mainly rely on glycolysis for energy. The prevention and treatment of T cell exhaustion is facing great challenges. Interfering T cell metabolism may achieve the goal of prevention and treatment of T cell exhaustion. In this review, we compiled the researches related to exhausted T cell metabolism and put forward the metabolic intervention strategies to reverse T cell exhaustion at different stages to achieve the purpose of preventing and treating T cell exhaustion.

scholarly journals Bovine Immunoinhibitory Receptors Contribute to Suppression of Mycobacterium avium subsp. paratuberculosis-Specific T-Cell Responses

2015 ◽  
Vol 84 (1) ◽  
pp. 77-89 ◽  
Author(s):  
Tomohiro Okagawa ◽  
Satoru Konnai ◽  
Asami Nishimori ◽  
Ryoyo Ikebuchi ◽  
Seiko Mizorogi ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mycobacterium Avium ◽  
T Cell Responses ◽  
T Cell Exhaustion ◽  
Content Type ◽  
Cell Exhaustion ◽  
Mhc Ii ◽  
Cell Responses ◽  
Ifn Γ

Johne's disease (paratuberculosis) is a chronic enteritis in cattle that is caused by intracellular infection withMycobacterium aviumsubsp.paratuberculosis. This infection is characterized by the functional exhaustion of T-cell responses toM. aviumsubsp.paratuberculosisantigens during late subclinical and clinical stages, presumably facilitating the persistence of this bacterium and the formation of clinical lesions. However, the mechanisms underlying T-cell exhaustion in Johne's disease are poorly understood. Thus, we performed expression and functional analyses of the immunoinhibitory molecules programmed death-1 (PD-1)/PD-ligand 1 (PD-L1) and lymphocyte activation gene 3 (LAG-3)/major histocompatibility complex class II (MHC-II) inM. aviumsubsp.paratuberculosis-infected cattle during the late subclinical stage. Flow cytometric analyses revealed the upregulation of PD-1 and LAG-3 in T cells in infected animals, which suffered progressive suppression of interferon gamma (IFN-γ) responses to theM. aviumsubsp.paratuberculosisantigen. In addition, PD-L1 and MHC-II were expressed on macrophages from infected animals, consistent with PD-1 and LAG-3 pathways contributing to the suppression of IFN-γ responses during the subclinical stages ofM. aviumsubsp.paratuberculosisinfection. Furthermore, dual blockade of PD-L1 and LAG-3 enhancedM. aviumsubsp.paratuberculosis-specific IFN-γ responses in blood from infected animals, andin vitroLAG-3 blockade enhanced IFN-γ production fromM. aviumsubsp.paratuberculosis-specific CD4+and CD8+T cells. Taken together, the present data indicate thatM. aviumsubsp.paratuberculosis-specific T-cell exhaustion is in part mediated by PD-1/PD-L1 and LAG-3/MHC-II interactions and that LAG-3 is a molecular target for the control ofM. aviumsubsp.paratuberculosis-specific T-cell responses.

scholarly journals Elevated coinhibitory molecule TIGIT mediates T cell exhaustion in septic patients

2021 ◽  
Author(s):  
Yini Sun ◽  
Renyu Ding ◽  
Yukun Chang ◽  
Jiuming Li ◽  
Xiaochun Ma
Keyword(s):  
T Cells ◽  
T Cell ◽  
Crucial Role ◽  
Cell Function ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Healthy Controls ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

Abstract Background: Sepsis-induced T cell exhaustion that is characterized by upregulated coinhibitory molecules and decreased cytokines release plays a crucial role in the immunosuppression during sepsis. Although PD-1 has shown a promising target to interfere with T cells dysfunction, the role of other coinhibitory receptors in sepsis remains largely elusive. Recently, it has been demonstrated that the coinhibitory molecule TIGIT more reliably identified exhausted T cells than PD-1. The aim of the study was to identify the expression of TIGIT on lymphocytes and the crucial role of TIGIT in modulating T cell function in septic patients. Methods: Twenty-five patients with sepsis and seventeen healthy controls were prospectively enrolled. Peripheral blood was obtained from septic patients within 24 hours after diagnosis of sepsis, as were healthy controls. TIGIT and other coinhibitory/costimulatory molecules expression on lymphocyte subsets was quantitated by flow cytometry. The relationship between TIGIT expression and clinical parameters was simultaneously evaluated. The function T cell from septic patients was assayed via stimulated cytokine secretion. Ex vivo functional assays were also conducted.Results: In the early stage of sepsis, patients exhibited higher levels of TIGIT on T cells relative to healthy donors, especially in the septic shock patients. Elevated frequencies of TIGIT + T cells positively correlated with the severity of organ failure and inflammatory responses in septic patients. TIGIT + T cells expressed higher levels of PD-1 and lower CD226. Further, elevated expression of TIGIT inhibited the release of cytokines including TNF, IFN-γ and IL-2 by CD4 + and CD8 + T cells. Strikingly, ex vivo blockade of TIGIT using anti-TIGIT antibody restored the frequencies of cytokine-producing T cells. Conclusions: These data illustrate TIGIT as a novel marker of exhausted T cells and suggest TIGIT may be a novel immunotherapeutic target during sepsis.

scholarly journals CXCL13 Correlates with Prognosis, Immune Infiltration, and T Cell Exhaustion in Ovarian Cancer

2021 ◽  
Author(s):  
Hailing Duan ◽  
Ying Lv ◽  
Pan Liao ◽  
Yiming Wang ◽  
Zhifang Zheng ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
Immune Cells ◽  
Gene Marker ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Immune Infiltration ◽  
Prognosis Prediction

Abstract Background: CXCL13 is an important chemotactic factor closely related to the biology of cancer cells. The presence work focused on exploring the significance of CXCL13 in prognosis prediction and analyzing the associations of CXCL13 with T cell function and immune infiltration in various cancers, especially ovarian cancer (OV).Purpose: CXCL13 is associated with prognosis, immune infiltration, and T cell failure of ovarian cancer.Methods: The Oncomine, GEPIA2 and HPA databases were utilized for analyzing CXCL13 levels within diverse cancers. The significance of CXCL13 in prognosis prediction was explored through Kaplan-Meier Plotter, TCGAportal, and GEPIA2. Meanwhile, the associations of CXCL13 with clinical stage, gene marker sets, and immune infiltration were examined through TISIDB, GEPIA2, and TIMER databases. Besides, CXCL13 was screened to analyze the biological processes (BPs) and KEGGs enriched by co-expression genes. The miRWalk database was employed for analyzing the gene-miRNA interaction network of CXCL13 within OV.Results: CXCL13 expression decreased in many cancers, which predicted the dismal survival of OV. CXCL13 upregulation was in direct proportion to the increased immune infiltration degrees of many functional T cells (like exhausted T cells) and immune cells. Additionally, some critical genes of exhausted T cells, such as TIM-3, PD-1, LAG3, TIGIT, GZMB, and CXCL13, were closely associated with CXCL13. Moreover, CXCL13 was related to immune response regulatory signaling pathway, leukocyte cell-cell adhesion, cell adhesion molecules (CAMs), and hematopoietic cell lineage. Conclusion: CXCL13 can serve as a biomarker to predict cancer prognosis, particularly OV. CXCL13 upregulation remarkably elevates the immune infiltration degrees of numerous immune cells, like mast cells, CD8+ T cells, natural killer (NK) cells, and dendritic cells (DCs). Furthermore, CXCL13 is suggested to be closely related to exhausted T cells, which may be used as a candidate regulating factor for T cell exhaustion within OV. Detecting CXCL13 levels contributes to prognosis prediction and CXCL13 regulation within exhausted T cells, which provides a new approach to maximizing the anti-OV efficacy of immunotherapy.

scholarly journals The Transcription Factor NFAT1 Participates in the Induction of CD4+ T Cell Functional Exhaustion during Plasmodium yoelii Infection

2017 ◽  
Vol 85 (9) ◽  
Author(s):  
Rachel Y. Ames ◽  
Li-Min Ting ◽  
Inessa Gendlina ◽  
Kami Kim ◽  
Fernando Macian
Keyword(s):  
T Cells ◽  
T Cell ◽  
Acute Infection ◽  
Plasmodium Yoelii ◽  
T Cell Exhaustion ◽  
Wild Type ◽  
Content Type ◽  
Cell Exhaustion ◽  
Cognate Antigen ◽  
Effector Cytokines

ABSTRACT Repeated stimulation of T cells that occurs in the context of chronic infection results in progressively reduced responsiveness of T cells to pathogen-derived antigens. This phenotype, known as T cell exhaustion, occurs during chronic infections caused by a variety of pathogens, from persistent viruses to parasites. Unlike the memory cells that typically form after successful pathogen clearance following an acute infection, exhausted T cells secrete lower levels of effector cytokines, proliferate less in response to cognate antigen, and upregulate cell surface inhibitory molecules such as PD-1 and LAG-3. The molecular events that lead to the induction of this phenotype have, however, not been fully characterized. In T cells, members of the NFAT family of transcription factors not only are responsible for the expression of many activation-induced genes but also are crucial for the induction of transcriptional programs that inhibit T cell activation and maintain tolerance. Here we show that NFAT1-deficient CD4+ T cells maintain higher proliferative capacity and expression of effector cytokines following Plasmodium yoelii infection and are therefore more resistant to P. yoelii-induced exhaustion than their wild-type counterparts. Consequently, gene expression microarray analysis of CD4+ T cells following P. yoelii-induced exhaustion shows upregulation of effector T cell-associated genes in the absence of NFAT1 compared with wild-type exhausted T cells. Furthermore, adoptive transfer of NFAT1-deficient CD4+ T cells into mice infected with P. yoelii results in increased production of antibodies to cognate antigen. Our results support the idea that NFAT1 is necessary to fully suppress effector responses during Plasmodium-induced CD4+ T cell exhaustion.

scholarly journals Expanded antigen-experienced CD160+CD8+effector T cells exhibit impaired effector functions in chronic lymphocytic leukemia

2021 ◽  
Vol 9 (4) ◽  
pp. e002189
Author(s):  
Najmeh Bozorgmehr ◽  
Isobel Okoye ◽  
Olaide Oyegbami ◽  
Lai Xu ◽  
Amelie Fontaine ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Effector T Cells ◽  
Lymphocytic Leukemia ◽  
Healthy Controls ◽  
T Cell Exhaustion ◽  
Inhibitory Receptors ◽  
Cell Exhaustion ◽  
Effector Functions ◽  
Cell Effector

BackgroundT cell exhaustion compromises antitumor immunity, and a sustained elevation of co-inhibitory receptors is a hallmark of T cell exhaustion in solid tumors. Similarly, upregulation of co-inhibitory receptors has been reported in T cells in hematological cancers such as chronic lymphocytic leukemia (CLL). However, the role of CD160, a glycosylphosphatidylinositol-anchored protein, as one of these co-inhibitory receptors has been contradictory in T cell function. Therefore, we decided to elucidate how CD160 expression and/or co-expression with other co-inhibitory receptors influence T cell effector functions in patients with CLL.MethodsWe studied 56 patients with CLL and 25 age-matched and sex-matched healthy controls in this study. The expression of different co-inhibitory receptors was analyzed in T cells obtained from the peripheral blood or the bone marrow. Also, we quantified the properties of extracellular vesicles (EVs) in the plasma of patients with CLL versus healthy controls. Finally, we measured 29 different cytokines, chemokines or other biomarkers in the plasma specimens of patients with CLL and healthy controls.ResultsWe found that CD160 was the most upregulated co-inhibitory receptor in patients with CLL. Its expression was associated with an exhausted T cell phenotype. CD160+CD8+ T cells were highly antigen-experienced/effector T cells, while CD160+CD4+ T cells were more heterogeneous. In particular, we identified EVs as a source of CD160 in the plasma of patients with CLL that can be taken up by T cells. Moreover, we observed a dominantly proinflammatory cytokine profile in the plasma of patients with CLL. In particular, interleukin-16 (IL-16) was highly elevated and correlated with the advanced clinical stage (Rai). Furthermore, we observed that the incubation of T cells with IL-16 results in the upregulation of CD160.ConclusionsOur study provides a novel insight into the influence of CD160 expression/co-expression with other co-inhibitory receptors in T cell effector functions in patients with CLL. Besides, IL-16-mediated upregulation of CD160 expression in T cells highlights the importance of IL-16/CD160 as potential immunotherapy targets in patients with CLL. Therefore, our findings propose a significant role for CD160 in T cell exhaustion in patients with CLL.

scholarly journals T-Cell Exhaustion Status Under High and Low Levels of Hypoxia-Inducible Factor 1α Expression in Glioma

2021 ◽  
Vol 12 ◽  
Author(s):  
Shuai Liu ◽  
Xing Liu ◽  
Chuanbao Zhang ◽  
Wei Shan ◽  
Xiaoguang Qiu
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cells ◽  
Hypoxia Inducible Factor ◽  
Lower Grade ◽  
T Cell Exhaustion ◽  
Expression Levels ◽  
Cell Exhaustion ◽  
Lower Grade Glioma ◽  
Genome Atlas

Background: Hypoxia-inducible factor 1α (HIF1A), the principal regulator of hypoxia, is involved in the suppression of antitumor immunity. We aimed to describe the T-cell exhaustion status of gliomas under different levels of HIF1A expression.Methods: In this study, 692 patients, whose data were collected from the Chinese Glioma Genome Atlas (CGGA) database, and 669 patients, whose data were collected from The Cancer Genome Atlas database, were enrolled. We further screened the data of a cohort of paired primary and recurrent patients from the CGGA dataset (n = 50). The abundance of immune cells was calculated using the transcriptome data. The association between HIF1A and T-cell exhaustion-related genes and immune cells was investigated.Results: According to the median value of HIF1A expression, gliomas were classified into low-HIF1A-expression and high-HIF1A-expression groups. The expression levels of PDL1 (CD274), FOXO1, and PRDM1 in the high-HIF1A-expression group were significantly higher in both glioblastoma (GBM) and lower-grade glioma. The abundance of exhausted T cells and B cells was significantly higher in the high-HIF1A-expression group, while that of macrophage, monocyte, and natural killer cell was significantly higher in the low-HIF1A-expression group in both GBM and lower-grade glioma. After tumor recurrence, the expression of HIF1A significantly increased, and the correlation between HIF1A expression levels and exhausted T cells and induced regulatory T cells became stronger.Conclusion: In diffuse gliomas, the levels of T-cell exhaustion-associated genes and the abundance of immune cells were elevated under high HIF1A expression. Reversing hypoxia may improve the efficacy of immunotherapy.

scholarly journals Treatment-Free Intervals Mitigate T-Cell Exhaustion Induced By Continuous CD19xCD3-BiTE® Construct Stimulation in Vitro

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 44-45
Author(s):  
Nora Zieger ◽  
Alyssa Nicholls ◽  
Jan Wulf ◽  
Gerulf Hänel ◽  
Maryam Kazerani Pasikhani ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Cell Function ◽  
Granzyme B ◽  
T Cell Exhaustion ◽  
Specific Lysis ◽  
Cell Exhaustion ◽  
T Cell Function

The bispecific T-cell engager (BiTE®) blinatumomab is approved for treatment of relapsed/refractory B-cell precursor acute lymphoblastic leukemia and applied as continuous infusion over 28 days. The overall response rate to blinatumomab reported in clinical trials was 43 % and correlated to T-cell expansion (Zugmaier et al. 2015). In chronic viral infections, continuous antigen stimulation induces T-cell exhaustion, defined by phenotypic changes and functional impairment (Wherry 2011). Thus, we hypothesized that continuous BiTE® construct stimulation leads to T-cell exhaustion and that a treatment-free interval (TFI) reverses progressive T-cell dysfunction. To simulate continuous application of a BiTE® construct in vitro, T-cell long-term co-cultures were set up. Healthy donor T cells were stimulated in the presence of CD19+ OCI-Ly1 cells for 28 days with AMG 562, a half-life extended CD19 and CD3 specific BiTE® construct. T cells were harvested from the co-culture every 3-4 days between day 7 and 28 and assessed for markers of T-cell exhaustion: (1) AMG 562-mediated cytotoxicity of T cells was evaluated as specific lysis of CD19+ Ba/F3 target cells after 3 days, (2) T-cell expansion during the cytotoxicity assay was calculated as fold change (FC) of CD2+ counts, (3) Cytokine secretion of AMG 562-stimulated T cells was evaluated in co-culture supernatants by cytometric bead array (CBA) or after PMA/Ionomycine stimulation via intracellular cytokine staining (ICCS), (4) T-cell metabolic fitness was determined by Mito- and Glycolytic Stress Test using a Seahorse Analyzer, and (5) expression of the exhaustion-related transcription factor TOX was assessed by multiparameter flow cytometry. In order to assess the effect of a TFI on T-cell function, we cultured T cells and CD19+ OCI-Ly1 cells in the absence of AMG 562 from day 7-14 and 21-28 and compared their activity to T cells stimulated continuously with AMG 562. On day 7 of continuous (CONT) AMG 562 stimulation, we observed high cytotoxic and proliferative potential (% specific lysis=93±0.2, FC=2.9±0.2) as well as high IFN-g and TNF-a secretion analyzed by ICCS (% CD8+IFN-g+TNF-a+=23±6.7). However, cytotoxicity and proliferation decreased gradually until day 28 (% specific lysis=28±8.9; FC=0.6±0.1). CBA analysis confirmed decreasing secretion of IFN-g (day 3: 61113±12482, day 24: 3085±1351 pg/ml) and TNF-a (day 3: 1160±567, day 24: 43±7.6 pg/ml) as well as decreased IL-2 and granzyme B levels in culture supernatants. We furthermore observed highest mitochondrial fitness and basal glycolysis in T cells on day 7 of stimulation (basal OCR=2.2±0.6, maximal OCR=3.7±1.0, SRC=1.5±1.1 pmol/min/1000 cells, basal ECAR=2.0±0.4 mpH/min/1000 cells) which decreased until day 28 (basal OCR=0.4±0.2, maximal OCR=1.5±0.5, SRC=1.0±0.2 pmol/min/1000 cells, basal ECAR=0.5±0.2 mpH/min/1000 cells). In concordance, TOX increased during continuous stimulation (MFI ratio CD8+ day 7=6±0.8 to 12±0.8 on day 28). Strikingly, implementation of a TFI of 7 days led to superior cytotoxicity in T cells compared to continuously stimulated T cells (% specific lysis on day 14 CONT=34±4.2, TFI=99±2.2) and granzyme B production (CD8+; MFI ratio on day 14 CONT=124±11, TFI=303±34). Furthermore, increased proliferation during the cytotoxicity assay was observed in previously rested T cells (FC CONT=0.2±0.0, TFI=1.6±0.6). Although T cell function also decreased over time in TFI T cells, they maintained a strikingly higher cytotoxic potential (CONT=6±4.4, TFI=52±9.9) as well as higher granzyme B production (CONT=25±2, TFI=170±11) on day 28 compared to continuously stimulated T cells. In addition, TFI T cells showed increased IFN-g and TNF-a secretion after PMA/Ionomycine stimulation on day 28 (% CD8+IFN-g+TNF-a+ CONT=21±3.8, TFI=38±11.6). Our in vitro results demonstrate that continuous AMG 562 exposure negatively impacts T-cell function. Comprehensive analysis of T-cell activity in an array of functional assays suggests that continuous BiTE® construct exposure leads to T-cell exhaustion which can be mitigated through TFI. Currently, T cells from patients receiving blinatumomab are being analyzed to confirm the clinical relevance of our findings. Furthermore, RNA-Seq of continuously vs. intermittently AMG 562-exposed T cells will help us to understand underlying transcriptional mechanisms of BiTE® construct induced T-cell exhaustion. Disclosures Zieger: AMGEN Research Munich: Research Funding. Buecklein:Pfizer: Consultancy; Novartis: Research Funding; Celgene: Research Funding; Amgen: Consultancy; Gilead: Consultancy, Research Funding. Brauchle:AMGEN Inc.: Research Funding. Marcinek:AMGEN Research Munich: Research Funding. Kischel:AMGEN: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Subklewe:Gilead Sciences: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Morphosys: Research Funding; Seattle Genetics: Research Funding; AMGEN: Consultancy, Honoraria, Research Funding; Janssen: Consultancy; Roche AG: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Honoraria.

Hemophagocytic lymphohistiocytosis in syntaxin-11–deficient mice: T-cell exhaustion limits fatal disease

Blood ◽  
2013 ◽  
Vol 121 (4) ◽  
pp. 604-613 ◽  
Author(s):  
Tamara Kögl ◽  
Jürgen Müller ◽  
Birthe Jessen ◽  
Annette Schmitt-Graeff ◽  
Gritta Janka ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Hemophagocytic Lymphohistiocytosis ◽  
Cytolytic Activity ◽  
T Cell Exhaustion ◽  
Inhibitory Receptors ◽  
Cell Exhaustion ◽  
Syntaxin 11 ◽  
Deficient Mice

Abstract Syntaxin-11 (Stx11), an atypical member of the SNARE protein family, is part of the cytolytic machinery of T and NK cells and involved in the fusion of lytic granules with the plasmamembrane. Functional loss of syntaxin-11 in humans causes defective degranulation and impaired cytolytic activity of T and NK cells. Furthermore, patients with STX11 deficiency develop familial hemophagocytic lymphohistiocytosis type 4 (FHL4), a life-threatening disease of severe hyperinflammation. We established Stx11-deficient mice as an animal model for FHL4. Stx11-deficient mice exhibited severely reduced degranulation and cytolytic activity of CTL and NK cells and developed all clinical symptoms of hemophagocytic lymphohistiocytosis (HLH) after infection with lymphocytic choriomeningitis virus (LCMV). The HLH phenotype was further characterized by hyperactive CD8 T cells and continuous IFN-γ production. However, in contrast to perforin-deficient mice, which represent a model for FHL2, progression of HLH was not fatal. Survival of Stx11-deficient mice was determined by exhaustion of antigen-specific T cells, characterized by expression of inhibitory receptors, sequential loss of effector functions, and finally T-cell deletion. Blockade of inhibitory receptors on T cells in Stx11-deficient mice converted nonfatal disease course into fatal HLH, identifying T-cell exhaustion as an important factor for determination of disease severity in HLH.

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