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1.
bioRxiv ; 2024 Jun 22.
Article in English | MEDLINE | ID: mdl-38948775

ABSTRACT

Patients aged 65 years and older account for an increasing proportion of patients with traumatic brain injury (TBI). Older TBI patients experience increased morbidity and mortality compared to their younger counterparts. Our prior data demonstrated that by blocking α4 integrin, anti-CD49d antibody (aCD49d Ab) abrogates CD8+ T-cell infiltration into the injured brain, improves survival, and attenuates neurocognitive deficits. Here, we aimed to uncover how aCD49d Ab treatment alters local cellular responses in the aged mouse brain. Consequently, mice incur age-associated toxic cytokine and chemokine responses long-term post-TBI. aCD49d Ab attenuates this response along with a T helper (Th)1/Th17 immunological shift and remediation of overall CD8+ T cell cytotoxicity. Furthermore, aCD49d Ab reduces CD8+ T cells exhibiting higher effector status, leading to reduced clonal expansion in aged, but not young, mouse brains with chronic TBI. Together, aCD49d Ab is a promising therapeutic strategy for treating TBI in the older people. Graphic abstract: Aged brains after TBI comprise two pools of CD8 + T cells . The aged brain has long been resided by a population of CD8 + T cells that's exhaustive and dysfunctional. Post TBI, due to BBB impairment, functional CD8 + T cells primarily migrate into the brain parenchyma. Aged, injury-associated microglia with upregulated MHC class I molecules can present neoantigens such as neuronal and/or myelin debris in the injured brains to functional CD8+ T, resulting in downstream CD8+ T cell cytotoxicity. aCD49d Ab treatment exerts its function by blocking the migration of functional effector CD8 + T cell population, leading to less cytotoxicity and resulting in improved TBI outcomes in aged mice.

2.
Front Vet Sci ; 11: 1406576, 2024.
Article in English | MEDLINE | ID: mdl-38840635

ABSTRACT

Introduction: Dehorning calves is necessary to minimize injury because intensive raising circumstances make horned cows more aggressive. However, acute pain is commonly perceived by farm animals when undergoing painful practices such as dehorning, affecting their health status and quality of life. By quantifying the magnitude of pain and discomfort associated with dehorning, we aim to contribute to a more humane and sustainable cattle farming industry. Methods: The objective of this study was to evaluate the behavioral, physiological, and emotional effects of acute dehorning pain in calves using two methods: dehorning cream and dehorning hot-iron.30 Holstein calves aged 4 days were selected for the study. These calves were randomly assigned to two experimental groups based on the method of disbudding: dehorning cream (n = 15) and hot-iron dehorning (n = 15). Before and after dehorning, we evaluated their physiological indicators of infrared eye temperature, concentrations of substance P, IL-6, cortisol, haptoglobin, as well as emotional state, and pain-related behavioral reactions. Results: Post-dehorning, the duration of lying down decreased significantly in both groups (DI and DC: 0-4 h) after dehorning (p < 0.05). Both groups exhibited increased frequencies of pain-related behaviors such as head shaking (DI: 1-7 h, DC: 1-6 h), ear flicking (DI: 2-7 h, DC: 2-7 h), head scratching (DI: 2-3 h, DC: 1-7 h), and top scuffing (DI: 2 h, DC: 2-7 h) compared to pre-dehorning (p < 0.05). The DC group demonstrated a higher frequency of head-shaking, ear-flicking, head-scratching, and top-rubbing behaviors, along with a longer duration of lying down (0-4 h), compared to the DI group (p < 0.05). Post-dehorning, play behavior reduced significantly in both groups (6-8 h) (p < 0.05), whereas judgment bias and fear levels showed no significant change (p > 0.05). Physiological measures including eye temperature, and blood levels of substance P and IL-6, did not differ significantly between the groups before and after dehorning (p > 0.05). However, 48 h after dehorning, calves in the DC group had significantly higher haptoglobin levels compared to the DI group (p = 0.015). Additionally, salivary cortisol levels in the DC group increased significantly at 3.5 h and 7 h post-dehorning (p = 0.018, p = 0.043). Discussion: Both hot-iron and cream dehorning induced pain in calves, as evidenced by increased pain-related behaviors, elevated salivary cortisol, and higher haptoglobin levels, alongside reduced positive behaviors. Notably, these effects were more pronounced in the DC group than in the DI group, suggesting that dehorning hot-iron may be a comparatively less stressful dehorning method for young calves. Moreover, the brief duration of pain response and weaker response to dehorning observed in 13-day-age calves in this study suggests that dehorning at younger ages may be more advisable and warrants further research.

3.
Front Immunol ; 15: 1399989, 2024.
Article in English | MEDLINE | ID: mdl-38799448

ABSTRACT

Introduction: Macrophage function is determined by microenvironment and origin. Brain and retinal microglia are both derived from yolk sac progenitors, yet their microenvironments differ. Utilizing single-cell RNA sequencing (scRNA-seq) data from mice, we tested the hypothesis that retinal and brain microglia exhibit distinct transcriptional profiles due to their unique microenvironments. Methods: Eyes and brains from 2-4 month wildtype mice were combined (20 eyes; 3 brains) to yield one biologically diverse sample per organ. Each tissue was digested into single cell suspensions, enriched for immune cells, and sorted for scRNA-seq. Analysis was performed in Seurat v3 including clustering, integration, and differential expression. Multi-parameter flow cytometry was used for validation of scRNA-seq results. Lymphocytic choriomeningitis virus (LCMV) Clone 13, which produces a systemic, chronic, and neurotropic infection, was used to validate scRNA-seq and flow cytometry results in vivo. Results: Cluster analysis of integrated gene expression data from eye and brain identified 6 Tmem119 + P2ry12 + microglial clusters. Differential expression analysis revealed that eye microglia were enriched for more pro-inflammatory processes including antigen processing via MHC class I (14.0-fold, H2-D1 and H2-K1) and positive regulation of T-cell immunity (8.4-fold) compared to brain microglia. Multi-parameter flow cytometry confirmed that retinal microglia expressed 3.2-fold greater H2-Db and 263.3-fold more H2-Kb than brain microglia. On Day 13 and 29 after LCMV infection, CD8+ T-cell density was greater in the retina than the brain. Discussion: Our data demonstrate that the microenvironment of retina and brain differs, resulting in microglia-specific gene expression changes. Specifically, retinal microglia express greater MHC class I by scRNA-seq and multi-parameter flow cytometry, resulting in a possibly enhanced capability to stimulate CD8+ T-cell inflammation during LCMV infection. These results may explain tissue-specific differences between retina and brain during systemic viral infections and CD8+ T-cell driven autoimmune disease.


Subject(s)
Brain , Microglia , Retina , Animals , Microglia/immunology , Microglia/metabolism , Mice , Retina/immunology , Retina/pathology , Brain/immunology , Brain/pathology , Brain/metabolism , Mice, Inbred C57BL , Lymphocytic choriomeningitis virus/immunology , Histocompatibility Antigens Class I/genetics , Histocompatibility Antigens Class I/immunology , Histocompatibility Antigens Class I/metabolism , T-Lymphocytes/immunology , Inflammation/immunology , Lymphocytic Choriomeningitis/immunology , Lymphocytic Choriomeningitis/virology , Single-Cell Analysis , CD8-Positive T-Lymphocytes/immunology , Transcriptome
4.
J Clin Invest ; 134(11)2024 Apr 25.
Article in English | MEDLINE | ID: mdl-38662453

ABSTRACT

Neuroinflammation is a recognized complication of immunotherapeutic approaches such as immune checkpoint inhibitor treatment, chimeric antigen receptor therapy, and graft versus host disease (GVHD) occurring after allogeneic hematopoietic stem cell transplantation. While T cells and inflammatory cytokines play a role in this process, the precise interplay between the adaptive and innate arms of the immune system that propagates inflammation in the central nervous system remains incompletely understood. Using a murine model of GVHD, we demonstrate that type 2 cannabinoid receptor (CB2R) signaling plays a critical role in the pathophysiology of neuroinflammation. In these studies, we identify that CB2R expression on microglial cells induces an activated inflammatory phenotype that potentiates the accumulation of donor-derived proinflammatory T cells, regulates chemokine gene regulatory networks, and promotes neuronal cell death. Pharmacological targeting of this receptor with a brain penetrant CB2R inverse agonist/antagonist selectively reduces neuroinflammation without deleteriously affecting systemic GVHD severity. Thus, these findings delineate a therapeutically targetable neuroinflammatory pathway and have implications for the attenuation of neurotoxicity after GVHD and potentially other T cell-based immunotherapeutic approaches.


Subject(s)
Graft vs Host Disease , Microglia , Neuroinflammatory Diseases , Receptor, Cannabinoid, CB2 , Animals , Mice , Allografts , Disease Models, Animal , Graft vs Host Disease/immunology , Graft vs Host Disease/pathology , Graft vs Host Disease/metabolism , Graft vs Host Disease/genetics , Hematopoietic Stem Cell Transplantation/adverse effects , Mice, Knockout , Microglia/metabolism , Microglia/immunology , Microglia/pathology , Neuroinflammatory Diseases/immunology , Neuroinflammatory Diseases/pathology , Neuroinflammatory Diseases/metabolism , Receptor, Cannabinoid, CB2/genetics , Receptor, Cannabinoid, CB2/metabolism , Receptor, Cannabinoid, CB2/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Male
5.
J Immunol ; 212(11): 1829-1842, 2024 Jun 01.
Article in English | MEDLINE | ID: mdl-38619295

ABSTRACT

In response to acute infection, naive CD4+ T cells primarily differentiate into T helper 1 (Th1) or T follicular helper (Tfh) cells that play critical roles in orchestrating cellular or humoral arms of immunity, respectively. However, despite the well established role of T-bet and BCL-6 in driving Th1 and Tfh cell lineage commitment, respectively, whether additional transcriptional circuits also underlie the fate bifurcation of Th1 and Tfh cell subsets is not fully understood. In this article, we study how the transcriptional regulator Bhlhe40 dictates the Th1/Tfh differentiation axis in mice. CD4+ T cell-specific deletion of Bhlhe40 abrogates Th1 but augments Tfh differentiation. We also assessed an increase in germinal center B cells and Ab production, suggesting that deletion of Bhlhe40 in CD4+ T cells not only alters Tfh differentiation but also their capacity to provide help to B cells. To identify molecular mechanisms by which Bhlhe40 regulates Th1 versus Tfh lineage choice, we first performed epigenetic profiling in the virus specific Th1 and Tfh cells following LCMV infection, which revealed distinct promoter and enhancer activities between the two helper cell lineages. Furthermore, we identified that Bhlhe40 directly binds to cis-regulatory elements of Th1-related genes such as Tbx21 and Cxcr6 to activate their expression while simultaneously binding to regions of Tfh-related genes such as Bcl6 and Cxcr5 to repress their expression. Collectively, our data suggest that Bhlhe40 functions as a transcription activator to promote Th1 cell differentiation and a transcription repressor to suppress Tfh cell differentiation.


Subject(s)
Basic Helix-Loop-Helix Transcription Factors , Cell Differentiation , T Follicular Helper Cells , Th1 Cells , Animals , Mice , Cell Differentiation/immunology , Cell Differentiation/genetics , Basic Helix-Loop-Helix Transcription Factors/genetics , Basic Helix-Loop-Helix Transcription Factors/metabolism , T Follicular Helper Cells/immunology , Th1 Cells/immunology , Mice, Knockout , Mice, Inbred C57BL , B-Lymphocytes/immunology , Lymphocytic Choriomeningitis/immunology , Lymphocytic Choriomeningitis/virology , Germinal Center/immunology , Proto-Oncogene Proteins c-bcl-6/genetics , Proto-Oncogene Proteins c-bcl-6/metabolism , Lymphocytic choriomeningitis virus/immunology , Receptors, CXCR5/genetics , Receptors, CXCR5/metabolism , Homeodomain Proteins
6.
Cell Rep Med ; 5(3): 101441, 2024 Mar 19.
Article in English | MEDLINE | ID: mdl-38428427

ABSTRACT

While immunotherapy has revolutionized cancer treatment, its safety has been hampered by immunotherapy-related adverse events. Unexpectedly, we show that Mediator complex subunit 1 (MED1) is required for T regulatory (Treg) cell function specifically in the tumor microenvironment. Treg cell-specific MED1 deletion does not predispose mice to autoimmunity or excessive inflammation. In contrast, MED1 is required for Treg cell promotion of tumor growth because MED1 is required for the terminal differentiation of effector Treg cells in the tumor. Suppression of these terminally differentiated Treg cells is sufficient for eliciting antitumor immunity. Both human and murine Treg cells experience divergent paths of differentiation in tumors and matched tissues with non-malignant inflammation. Collectively, we identify a pathway promoting the differentiation of a Treg cell effector subset specific to tumors and demonstrate that suppression of a subset of Treg cells is sufficient for promoting antitumor immunity in the absence of autoimmune consequences.


Subject(s)
Neoplasms , T-Lymphocytes, Regulatory , Humans , Animals , Mice , Mediator Complex Subunit 1/metabolism , Forkhead Transcription Factors , Neoplasms/pathology , Inflammation/metabolism , Tumor Microenvironment
7.
Nat Immunol ; 25(2): 191-193, 2024 Feb.
Article in English | MEDLINE | ID: mdl-38238607
8.
Immune Netw ; 23(5): e41, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37970230

ABSTRACT

CD4 and CD8 T cells are key players in the immune response against both pathogenic infections and cancer. CD4 T cells provide help to CD8 T cells via multiple mechanisms, including licensing dendritic cells (DCs), co-stimulation, and cytokine production. During acute infection and vaccination, CD4 T cell help is important for the development of CD8 T cell memory. However, during chronic viral infection and cancer, CD4 helper T cells are critical for the sustained effector CD8 T cell response, through a variety of mechanisms. In this review, we focus on T cell responses in conditions of chronic Ag stimulation, such as chronic viral infection and cancer. In particular, we address the significant role of CD4 T cell help in promoting effector CD8 T cell responses, emerging techniques that can be utilized to further our understanding of how these interactions may take place in the context of tertiary lymphoid structures, and how this key information can be harnessed for therapeutic utility against cancer.

9.
Nat Commun ; 14(1): 6597, 2023 10 18.
Article in English | MEDLINE | ID: mdl-37852965

ABSTRACT

Influenza virus infection causes increased morbidity and mortality in the elderly. Aging impairs the immune response to influenza, both intrinsically and because of altered interactions with endothelial and pulmonary epithelial cells. To characterize these changes, we performed single-cell RNA sequencing (scRNA-seq), spatial transcriptomics, and bulk RNA sequencing (bulk RNA-seq) on lung tissue from young and aged female mice at days 0, 3, and 9 post-influenza infection. Our analyses identified dozens of key genes differentially expressed in kinetic, age-dependent, and cell type-specific manners. Aged immune cells exhibited altered inflammatory, memory, and chemotactic profiles. Aged endothelial cells demonstrated characteristics of reduced vascular wound healing and a prothrombotic state. Spatial transcriptomics identified novel profibrotic and antifibrotic markers expressed by epithelial and non-epithelial cells, highlighting the complex networks that promote fibrosis in aged lungs. Bulk RNA-seq generated a timeline of global transcriptional activity, showing increased expression of genes involved in inflammation and coagulation in aged lungs. Our work provides an atlas of high-throughput sequencing methodologies that can be used to investigate age-related changes in the response to influenza virus, identify novel cell-cell interactions for further study, and ultimately uncover potential therapeutic targets to improve health outcomes in the elderly following influenza infection.


Subject(s)
Influenza, Human , Orthomyxoviridae Infections , Humans , Female , Animals , Mice , Aged , Endothelial Cells , Lung/metabolism , Epithelial Cells/metabolism
10.
Animals (Basel) ; 13(19)2023 Sep 26.
Article in English | MEDLINE | ID: mdl-37835629

ABSTRACT

Environmental enrichment can improve animal welfare. As a method of environmental enrichment, the effect of different auditory stimulations on the behavior response and welfare of laying hen chicks has yet to be investigated. Therefore, this study was aimed at exploring the impact of various auditory exposures on the behavior, learning ability, and fear response of 4-week-old laying hen chicks. A total of 600 1-day-old chicks were randomly assigned to five different groups: C (control group), LM (Mozart's String Quartets, 65 to 75 dB), LN (recorded ventilation fans and machinery, 65 to 75 dB), HN (recorded ventilation fans and machinery, 85 to 95 dB), and HM (Mozart's String Quartets, 85 to 95 dB). The experiment was conducted from day 1 until the end of the experiment on day 28. Groups LM and LN were exposed to music and noise stimulation ranging from 65 to 75 dB. Groups HN and HM, meanwhile, received noise and music stimulation ranging from 85 to 95 dB. The control group (C) did not receive any additional auditory stimuli. During the experimental period, continuous behavioral recordings were made of each group of chicks from day 22 to day 28. On day 21, the PAL (one-trial passive avoidance learning) task was conducted. On days 23 and 24, OF (open field) and TI (tonic immobility) tests were performed, and the levels of serum CORT (corticosterone) and DA (dopamine) were measured. The results indicated that exposure to music and noise at intensities ranging from 85 to 95 dB could reduce comforting, preening, PAL avoidance rate, the total number of steps and grid crossings of OF, and the concentration of DA in 4 WOA chicks (p < 0.05), increase the freezing times of OF (p < 0.05); 65 to 75 dB of noise stimulation could reduce preening and total number steps of OF in 4 WOA chicks (p < 0.05), increase the freezing times of OF (p < 0.05); and 65 to 75 dB of music exposure could reduce the concentration of CORT in 4 WOA chicks (p < 0.05). Therefore, 65 to 75 dB of music exposure could produce positive effects on chicks and showed relatively low CORT level, whereas 85 to 95 dB of music and noise exposure could reduce comforting and preening behavior, impair learning ability, and increase the fear responses of chicks.

11.
Res Pract Thromb Haemost ; 7(6): 102164, 2023 Aug.
Article in English | MEDLINE | ID: mdl-37680312

ABSTRACT

Background: Patients with COVID-19 have a higher risk of thrombosis and thromboembolism, but the underlying mechanism(s) remain to be fully elucidated. In patients with COVID-19, high lipoprotein(a) (Lp(a)) is positively associated with the risk of ischemic heart disease. Lp(a), composed of an apoB-containing particle and apolipoprotein(a) (apo(a)), inhibits the key fibrinolytic enzyme, tissue-type plasminogen activator (tPA). However, whether the higher Lp(a) associates with lower tPA activity, the longitudinal changes of these parameters in hospitalized patients with COVID-19, and their correlation with clinical outcomes are unknown. Objectives: To assess if Lp(a) associates with lower tPA activity in COVID-19 patients, and how in COVID-19 populations Lp(a) and tPA change post infection. Methods: Endogenous tPA enzymatic activity, tPA or Lp(a) concentration were measured in plasma from hospitalized patients with and without COVID-19. The association between plasma tPA and adverse clinical outcomes was assessed. Results: In hospitalized patients with COVID-19, we found lower tPA enzymatic activity and higher plasma Lp(a) than that in non-COVID-19 controls. During hospitalization, Lp(a) increased and tPA activity decreased, which associates with mortality. Among those who survived, Lp(a) decreased and tPA enzymatic activity increased during recovery. In patients with COVID-19, tPA activity is inversely correlated with tPA concentrations, thus, in another larger COVID-19 cohort, we utilized plasma tPA concentration as a surrogate to inversely reflect tPA activity. The tPA concentration was positively associated with death, disease severity, plasma inflammatory, and prothrombotic markers, and with length of hospitalization among those who were discharged. Conclusion: High Lp(a) concentration provides a possible explanation for low endogenous tPA enzymatic activity, and poor clinical outcomes in patients with COVID-19.

12.
bioRxiv ; 2023 Aug 14.
Article in English | MEDLINE | ID: mdl-37645843

ABSTRACT

Neuroinflammation is a recognized complication of immunotherapeutic approaches such as immune checkpoint inhibitor treatment, chimeric antigen receptor therapy, and graft versus host disease (GVHD) occurring after allogeneic hematopoietic stem cell transplantation. While T cells and inflammatory cytokines play a role in this process, the precise interplay between the adaptive and innate arms of the immune system that propagates inflammation in the central nervous system remains incompletely understood. Using a murine model of GVHD, we demonstrate that type 2 cannabinoid receptor (CB2R) signaling plays a critical role in the pathophysiology of neuroinflammation. In these studies, we identify that CB2R expression on microglial cells induces an activated inflammatory phenotype which potentiates the accumulation of donor-derived proinflammatory T cells, regulates chemokine gene regulatory networks, and promotes neuronal cell death. Pharmacological targeting of this receptor with a brain penetrant CB2R inverse agonist/antagonist selectively reduces neuroinflammation without deleteriously affecting systemic GVHD severity. Thus, these findings delineate a therapeutically targetable neuroinflammatory pathway and has implications for the attenuation of neurotoxicity after GVHD and potentially other T cell-based immunotherapeutic approaches.

13.
Adv Sci (Weinh) ; 10(28): e2206692, 2023 Oct.
Article in English | MEDLINE | ID: mdl-37587835

ABSTRACT

Regulatory T (Treg) cells are inevitable to prevent deleterious immune responses to self and commensal microorganisms. Treg function requires continuous expression of the transcription factor (TF) FOXP3 and is divided into two major subsets: resting (rTregs) and activated (aTregs). Continuous T cell receptor (TCR) signaling plays a vital role in the differentiation of aTregs from their resting state, and in their immune homeostasis. The process by which Tregs differentiate, adapt tissue specificity, and maintain stable phenotypic expression at the transcriptional level is still inconclusivei. In this work, the role of BATF is investigated, which is induced in response to TCR stimulation in naïve T cells and during aTreg differentiation. Mice lacking BATF in Tregs developed multiorgan autoimmune pathology. As a transcriptional regulator, BATF is required for Treg differentiation, homeostasis, and stabilization of FOXP3 expression in different lymphoid and non-lymphoid tissues. Epigenetically, BATF showed direct regulation of Treg-specific genes involved in differentiation, maturation, and tissue accumulation. Most importantly, FOXP3 expression and Treg stability require continuous BATF expression in Tregs, as it regulates demethylation and accessibility of the CNS2 region of the Foxp3 locus. Considering its role in Treg stability, BATF should be considered an important therapeutic target in autoimmune disease.


Subject(s)
Autoimmune Diseases , T-Lymphocytes, Regulatory , Mice , Animals , Cell Differentiation , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Receptors, Antigen, T-Cell/metabolism
14.
Animals (Basel) ; 13(16)2023 Aug 14.
Article in English | MEDLINE | ID: mdl-37627406

ABSTRACT

Transcription factor Homeobox C8 (HOXC8) is identified as a white adipose gene as revealed by expression profile analysis in fat tissues. However, the specific role of HOXC8 in fat accumulation remains to be identified. This study was designed to reveal the effects of HOXC8 on preadipocyte proliferation and differentiation. We first make clear that the expression of HOXC8 is associated with fat contents in muscles, highlighting a role of HOXC8 in fat accumulation. Next, it is demonstrated that HOXC8 promotes the proliferation and differentiation of preadipocytes through gain- and loss-of-function assays in primary cultured porcine preadipocytes. Then, mechanisms underlying the regulation of HOXC8 on preadipocyte proliferation and differentiation are identified with RNA sequencing, and a number of differentially expressed genes (DEGs) in response to HOXC8 knockdown are identified. The top GO (Gene Ontology) terms enriched by DEGs involved in proliferation and differentiation, respectively, are identical. IL-17 signaling pathway is the common one significantly enriched by DEGs involved in preadipocyte proliferation and differentiation, respectively, indicating its importance in mediating fat accumulation regulated by HOXC8. Additionally, we find that the inhibition of proliferation is one of the main processes during preadipocyte differentiation. The results will contribue to further revealing the mechanisms underlying fat accumulation regulated by HOXC8.

15.
Cell Rep ; 42(6): 112649, 2023 06 27.
Article in English | MEDLINE | ID: mdl-37330910

ABSTRACT

During chronic viral infection and cancer, it has been established that a subset of progenitor CD8+ T cells continuously gives rise to terminally exhausted cells and cytotoxic effector cells. Although multiple transcriptional programs governing the bifurcated differentiation trajectories have been previously studied, little is known about the chromatin structure changes regulating CD8+ T cell-fate decision. In this study, we demonstrate that the chromatin remodeling complex PBAF restrains expansion and promotes exhaustion of CD8+ T cells during chronic viral infection and cancer. Mechanistically, transcriptomic and epigenomic analyses reveal the role of PBAF in maintaining chromatin accessibility of multiple genetic pathways and transcriptional programs to restrain proliferation and promote T cell exhaustion. Harnessing this knowledge, we demonstrate that perturbation of PBAF complex constrained exhaustion and promoted expansion of tumor-specific CD8+ T cells resulting in antitumor immunity in a preclinical melanoma model, implicating PBAF as an attractive target for cancer immunotherapeutic.


Subject(s)
Melanoma , Virus Diseases , Humans , CD8-Positive T-Lymphocytes , Cell Differentiation , Melanoma/metabolism , Persistent Infection , Transcription Factors/metabolism , Virus Diseases/metabolism , Animals , Mice
16.
Trends Immunol ; 44(4): 276-286, 2023 04.
Article in English | MEDLINE | ID: mdl-36907685

ABSTRACT

Reinvigorating the function of exhausted CD8+ T cells during chronic viral infection and cancer is a major goal of current immunotherapy regimens. Here, we discuss recent advances in our understanding of exhausted CD8+ T cell heterogeneity as well as the potential differentiation trajectories that exhausted T cells follow during chronic infection and/or cancer. We highlight surmounting evidence suggesting that some T cell clones are divergent in nature and can develop into either terminally differentiated effector or exhausted CD8+ T cells. Lastly, we consider the potential therapeutic implications of such a bifurcation model of CD8+ T cell differentiation, including the intriguing hypothesis that redirecting progenitor CD8+ T cell differentiation along an effector pathway may serve as a novel approach to mitigate T cell exhaustion.


Subject(s)
Lymphocytic Choriomeningitis , Neoplasms , Humans , CD8-Positive T-Lymphocytes/metabolism , Lymphocytic Choriomeningitis/metabolism , Lymphocytic choriomeningitis virus/physiology , Cell Differentiation
17.
J Immunol ; 210(9): 1281-1291, 2023 05 01.
Article in English | MEDLINE | ID: mdl-36920384

ABSTRACT

Diacylglycerol is a potent element of intracellular secondary signaling cascades whose production is enhanced by cell-surface receptor agonism and function is regulated by enzymatic degradation by diacylglycerol kinases (DGKs). In T cells, stringent regulation of the activity of this second messenger maintains an appropriate balance between effector function and anergy. In this article, we demonstrate that DGKα is an indispensable regulator of TCR-mediated activation of CD8 T cells in lymphocytic choriomeningitis virus Clone 13 viral infection. In the absence of DGKα, Clone 13 infection in a murine model results in a pathologic, proinflammatory state and a multicellular immunopathologic host death that is predominantly driven by CD8 effector T cells.


Subject(s)
Lymphocytic Choriomeningitis , Lymphocytic choriomeningitis virus , Mice , Animals , Diacylglycerol Kinase/genetics , Diacylglycerol Kinase/metabolism , Diglycerides/metabolism , Lymphocytic Choriomeningitis/metabolism , CD8-Positive T-Lymphocytes/metabolism , Clone Cells , Mice, Inbred C57BL , Mice, Knockout
18.
Angiogenesis ; 26(2): 265-278, 2023 05.
Article in English | MEDLINE | ID: mdl-36403190

ABSTRACT

Overcoming vascular immunosuppression: lack of endothelial cell (EC) responsiveness to inflammatory stimuli in the proangiogenic environment of tumors, is essential for successful cancer immunotherapy. The mechanisms through which Vascular Endothelial Growth Factor A(VEGF-A) modulates tumor EC response to exclude T-cells are not well understood. Here, we demonstrate that EC-specific deletion of small GTPase Rap1B, previously implicated in normal angiogenesis, restricts tumor growth in endothelial-specific Rap1B-knockout (Rap1BiΔEC) mice. EC-specific Rap1B deletion inhibits angiogenesis, but also leads to an altered tumor microenvironment with increased recruitment of leukocytes and increased activity of tumor CD8+ T-cells. Depletion of CD8+ T-cells restored tumor growth in Rap1BiΔEC mice. Mechanistically, global transcriptome and functional analyses indicated upregulation of signaling by a tumor cytokine, TNF-α, and increased NF-κB transcription in Rap1B-deficient ECs. Rap1B-deficiency led to elevated proinflammatory chemokine and Cell Adhesion Molecules (CAMs) expression in TNF-α stimulated ECs. Importantly, CAM expression was elevated in tumor ECs from Rap1BiΔEC mice. Significantly, Rap1B deletion prevented VEGF-A-induced immunosuppressive downregulation of CAM expression, demonstrating that Rap1B is essential for VEGF-A-suppressive signaling. Thus, our studies identify a novel endothelial-endogenous mechanism underlying VEGF-A-dependent desensitization of EC to proinflammatory stimuli. Significantly, they identify EC Rap1B as a potential novel vascular target in cancer immunotherapy.


Subject(s)
CD8-Positive T-Lymphocytes , Endothelial Cells , Neoplasms , rap GTP-Binding Proteins , Animals , Mice , CD8-Positive T-Lymphocytes/immunology , Immunosuppression Therapy , Neoplasms/blood supply , Neoplasms/genetics , Neoplasms/immunology , Tumor Microenvironment/genetics , Tumor Microenvironment/immunology , Tumor Necrosis Factor-alpha/genetics , Tumor Necrosis Factor-alpha/immunology , Vascular Endothelial Growth Factor A/genetics , Vascular Endothelial Growth Factor A/immunology , Endothelial Cells/immunology , Endothelial Cells/physiology , NF-kappa B/genetics , NF-kappa B/immunology , rap GTP-Binding Proteins/genetics , rap GTP-Binding Proteins/immunology
19.
J Exp Med ; 220(1)2023 01 02.
Article in English | MEDLINE | ID: mdl-36315049

ABSTRACT

Although recent evidence demonstrates heterogeneity among CD8+ T cells during chronic infection, developmental relationships and mechanisms underlying their fate decisions remain incompletely understood. Using single-cell RNA and TCR sequencing, we traced the clonal expansion and differentiation of CD8+ T cells during chronic LCMV infection. We identified immense clonal and phenotypic diversity, including a subset termed intermediate cells. Trajectory analyses and infection models showed intermediate cells arise from progenitor cells before bifurcating into terminal effector and exhausted subsets. Genetic ablation experiments identified that type I IFN drives exhaustion through an IRF7-dependent mechanism, possibly through an IFN-stimulated subset bridging progenitor and exhausted cells. Conversely, Zeb2 was critical for generating effector cells. Intriguingly, some T cell clones exhibited lineage bias. Mechanistically, we identified that TCR avidity correlates with an exhausted fate, whereas SHP-1 selectively restricts low-avidity effector cell accumulation. Thus, our work elucidates novel mechanisms underlying CD8+ T cell fate determination during persistent infection and suggests two potential pathways leading to exhaustion.


Subject(s)
CD8-Positive T-Lymphocytes , Persistent Infection , Humans , CD8-Positive T-Lymphocytes/metabolism , Cells, Cultured , Cell Differentiation , Receptors, Antigen, T-Cell/metabolism
20.
Immunity ; 55(12): 2369-2385.e10, 2022 12 13.
Article in English | MEDLINE | ID: mdl-36370712

ABSTRACT

Type I and II interferons (IFNs) stimulate pro-inflammatory programs that are critical for immune activation, but also induce immune-suppressive feedback circuits that impede control of cancer growth. Here, we sought to determine how these opposing programs are differentially induced. We demonstrated that the transcription factor interferon regulatory factor 2 (IRF2) was expressed by many immune cells in the tumor in response to sustained IFN signaling. CD8+ T cell-specific deletion of IRF2 prevented acquisition of the T cell exhaustion program within the tumor and instead enabled sustained effector functions that promoted long-term tumor control and increased responsiveness to immune checkpoint and adoptive cell therapies. The long-term tumor control by IRF2-deficient CD8+ T cells required continuous integration of both IFN-I and IFN-II signals. Thus, IRF2 is a foundational feedback molecule that redirects IFN signals to suppress T cell responses and represents a potential target to enhance cancer control.


Subject(s)
Interferon Type I , Neoplasms , Humans , Interferon Regulatory Factor-2/genetics , CD8-Positive T-Lymphocytes , Transcription Factors , T-Cell Exhaustion , Neoplasms/pathology
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