Themis controls T cell activation, effector functions, and metabolism of peripheral CD8+ T cells
Ontology highlight
ABSTRACT:
SUBMITTER:
PROVIDER: S-EPMC10517225 | biostudies-literature | 2023 Sep
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Although cancer immunotherapy is effective against hematological malignancies, it is less effective against solid tumors due in part to significant metabolic challenges present in the tumor microenvironment (TME), where infiltrated CD8+ T cells face fierce competition with cancer cells for limited nutrients. Strong metabolic suppression in the TME is often associated with impaired T cell recruitment to the tumor site and hyporesponsive effector function via T cell exhaustion. Increasing evidence suggests that mitochondria play a key role in CD8+ T cell activation, effector function, and persistence in tumors. In this study, we showed that there was an increase in overall mitochondrial function, including mitochondrial mass and membrane potential, during both mouse and human CD8+ T cell activation. CD8+ T cell mitochondrial membrane potential was closely correlated with granzyme B and IFN-γ production, demonstrating the significance of mitochondria in effector T cell function. Additionally, activated CD8+ T cells that migrate on ICAM-1 and CXCL12 consumed significantly more oxygen than stationary CD8+ T cells. Inhibition of mitochondrial respiration decreased the velocity of CD8+ T cell migration, indicating the importance of mitochondrial metabolism in CD8+ T cell migration. Remote optical stimulation of CD8+ T cells that express our newly developed "OptoMito-On" successfully enhanced mitochondrial ATP production and improved overall CD8+ T cell migration and effector function. Our study provides new insight into the effect of the mitochondrial membrane potential on CD8+ T cell effector function and demonstrates the development of a novel optogenetic technique to remotely control T cell metabolism and effector function at the target tumor site with outstanding specificity and temporospatial resolution.
| S-EPMC8209468 | biostudies-literature
Project description:Themis is a T cell lineage-specific molecule that is involved in TCR signal transduction. The effects of germline Themis deletion on peripheral CD4+ T cell function have not been described before. In this study, we found that Themis-deficient CD4+ T cells had poor proliferative responses, reduced cytokine production in vitro and weaker inflammatory potential, as measured by their ability to cause colitis in vivo. Resting T cells are quiescent, whereas activated T cells have high metabolic demands. Fulfillment of these metabolic demands depends upon nutrient availability and upregulation of nutrient intake channels after efficient TCR signal transduction, which leads to metabolic reprogramming in T cells. We tested whether defects in effector functions were caused by impaired metabolic shifts in Themis-deficient CD4+ T cells due to inefficient TCR signal transduction, in turn caused by the lack of Themis. We found that upon TCR stimulation, Themis-deficient CD4+ T cells were unable to upregulate the expression of insulin receptor (IR), glucose transporter (GLUT1), the neutral amino acid transporter CD98 and the mTOR pathway, as measured by c-Myc and pS6 expression. Mitochondrial analysis of activated Themis-deficient CD4+ T cells showed more oxidative phosphorylation (OXPHOS) than aerobic glycolysis, indicating defective metabolic reprogramming. Furthermore, we found reduced NFAT translocation in Themis-deficient CD4+ T cells upon TCR stimulation. Using previously reported ChIP-seq and RNA-seq data, we found that NFAT nuclear translocation controls IR gene expression. Together, our results describe an internal circuit between TCR signal transduction, NFAT nuclear translocation, and metabolic signaling in CD4+ T cells.
| S-EPMC8429700 | biostudies-literature
Project description:The transcription factor IRF4 is required for CD8+ T cell activation, proliferation, and differentiation to effector cells and thus is essential for robust CD8+ T cell responses. The function of IRF4 in memory CD8+ T cells yet needs to be explored. To investigate the role of IRF4 for maintaining differentiation state and survival of CD8+ memory T cells, we used a mouse model with tamoxifen-inducible Irf4 knockout to preclude effects due to inefficient memory cell differentiation in absence of IRF4. We infected mice with ovalbumin-recombinant listeria and induced Irf4 knockout after clearance of the pathogen. Loss of IRF4 resulted in phenotypical changes of CD8+ memory T cells but did not cause a reduction of the total memory T cell population. However, upon reencounter of the pathogen, CD8+ memory T cells showed impaired expansion and acquisition of effector functions. When compared to CD8+ effector memory T cells, CD8+ tissue-resident memory T cells (TRM cells) expressed higher IRF4 levels. Mice with constitutive Irf4 knockout had diminished CD8+ TRM-cell populations, and tamoxifen-induced Irf4 deletion caused a reduction of this cell population. In conclusion, our results demonstrate that IRF4 is required for effective reactivation but not for general survival of CD8+ memory T cells. Formation and maintenance of CD8+ TRM cells, in contrast, appear to depend on IRF4.
| S-EPMC8072204 | biostudies-literature
Project description:Memory CD8+ T cells are indispensable for maintaining long-term immunity against intracellular pathogens and tumors. Despite their presence at oxygen-deprived infected tissue sites or in tumors, the impact of local oxygen pressure on memory CD8+ T cells remains largely unclear. We sought to elucidate how oxygen pressure impacts memory CD8+ T cells arising after infection with Listeria monocytogenes-OVA. Our data revealed that reduced oxygen pressure during in vitro culture switched CD8+ T cell metabolism from oxidative phosphorylation to a glycolytic phenotype. Quantitative proteomic analysis showed that limiting oxygen conditions increased the expression of glucose transporters and components of the glycolytic pathway, while decreasing TCA cycle and mitochondrial respiratory chain proteins. The altered CD8+ T cell metabolism did not affect the expansion potential, but enhanced the granzyme B and IFN-γ production capacity. In vivo, memory CD8+ T cells cultured under low oxygen pressure provided protection against bacterial rechallenge. Taken together, our study indicates that strategies of cellular immune therapy may benefit from reducing oxygen during culture to develop memory CD8+ T cells with superior effector functions.
| S-EPMC10108084 | biostudies-literature
Project description:In inflammatory blood vessel diseases, macrophages represent a key component of the vascular infiltrates and are responsible for tissue injury and wall remodeling. To examine whether inflammatory macrophages in the vessel wall display a single distinctive effector program, we compared functional profiles in patients with either coronary artery disease (CAD) or giant cell arteritis (GCA). Unexpectedly, monocyte-derived macrophages from the 2 patient cohorts displayed disease-specific signatures and differed fundamentally in metabolic fitness. Macrophages from CAD patients were high producers for T cell chemoattractants (CXCL9, CXCL10), the cytokines IL-1β and IL-6, and the immunoinhibitory ligand PD-L1. In contrast, macrophages from GCA patients upregulated production of T cell chemoattractants (CXCL9, CXCL10) but not IL-1β and IL-6, and were distinctly low for PD-L1 expression. Notably, disease-specific effector profiles were already identifiable in circulating monocytes. The chemokinehicytokinehiPD-L1hi signature in CAD macrophages was sustained by excess uptake and breakdown of glucose, placing metabolic control upstream of inflammatory function. We conclude that monocytes and macrophages contribute to vascular inflammation in a disease-specific and discernible pattern, have choices to commit to different functional trajectories, are dependent on glucose availability in their immediate microenvironment, and possess memory in their lineage commitment. Supported by the NIH (R01 AR042527, R01 HL117913, R01 AI108906, P01 HL129941, R01 AI108891, R01 AG045779 U19 AI057266, R01 AI129191), I01 BX001669, and the Cahill Discovery Fund.
| S-EPMC6237479 | biostudies-literature
Project description:We previously reported that the inhibition of stearoyl-CoA desaturase 1 (SCD1) enhances the antitumor function of CD8+ T cells indirectly via restoring production of DC recruiting chemokines by cancer cells and subsequent induction of antitumor CD8+ T cells. In this study, we investigated the molecular mechanism of direct enhancing effects of SCD1 inhibitors on CD8+ T cells. In vitro treatment of CD8+ T cells with SCD1 inhibitors enhanced IFN-γ production and cytotoxic activity of T cells along with decreased oleic acid and esterified cholesterol, which is generated by cholesterol esterase, acetyl-CoA acetyltransferase 1 (ACAT1), in CD8+ T cells. The addition of oleic acid or cholesteryl oleate reversed the enhanced functions of CD8+ T cells treated with SCD1 inhibitors. Systemic administration of SCD1 inhibitor to MCA205 tumor-bearing mice enhanced IFN-γ production of tumor-infiltrating CD8+ T cells, in which oleic acid and esterified cholesterol, but not cholesterol, were decreased. These results indicated that SCD1 suppressed effector functions of CD8+ T cells through the increased esterified cholesterol in an ACAT1-dependent manner, and SCD1 inhibition enhanced T cell activity directly through decreased esterified cholesterol. Finally, SCD1 inhibitors or ACAT1 inhibitors synergistically enhanced the antitumor effects of anti-PD-1 antibody therapy or CAR-T cell therapy in mouse tumor models. Therefore, the SCD1-ACAT1 axis is regulating effector functions of CD8+ T cells, and SCD1 inhibitors, and ACAT1 inhibitors are attractive drugs for cancer immunotherapy.
| S-EPMC10823278 | biostudies-literature
Project description:Protein kinase CK2 is a serine/threonine kinase composed of two catalytic subunits (CK2α and/or CK2α') and two regulatory subunits (CK2β). CK2 promotes cancer progression by activating the NF-κB, PI3K/AKT/mTOR, and JAK/STAT pathways, and also is critical for immune cell development and function. The potential involvement of CK2 in CD8+ T cell function has not been explored. We demonstrate that CK2 protein levels and kinase activity are enhanced upon mouse CD8+ T cell activation. CK2α deficiency results in impaired CD8+ T cell activation and proliferation upon TCR stimulation. Furthermore, CK2α is involved in CD8+ T cell metabolic reprogramming through regulating the AKT/mTOR pathway. Lastly, using a mouse Listeria monocytogenes infection model, we demonstrate that CK2α is required for CD8+ T cell expansion, maintenance, and effector function in both primary and memory immune responses. Collectively, our study implicates CK2α as an important regulator of mouse CD8+ T cell activation, metabolic reprogramming, and differentiation both in vitro and in vivo.
| S-EPMC9492634 | biostudies-literature
Project description:An unresolved issue in autoimmunity is the lack of surrogate biomarkers of immunological self-tolerance for disease monitoring. Here, we show that peripheral frequency of a regulatory T cell population, characterized by the co-expression of CD3 and CD56 molecules (TR3-56), is reduced in subjects with new-onset type 1 diabetes (T1D). In three independent T1D cohorts, we find that low frequency of circulating TR3-56 cells is associated with reduced β-cell function and with the presence of diabetic ketoacidosis. As autoreactive CD8+ T cells mediate disruption of insulin-producing β-cells1-3, we demonstrate that TR3-56 cells can suppress CD8+ T cell functions in vitro by reducing levels of intracellular reactive oxygen species. The suppressive function, phenotype and transcriptional signature of TR3-56 cells are also altered in T1D children. Together, our findings indicate that TR3-56 cells constitute a regulatory cell population that controls CD8+ effector functions, whose peripheral frequency may represent a traceable biomarker for monitoring immunological self-tolerance in T1D.
| S-EPMC7272221 | biostudies-literature
Project description:Natural killer (NK) cells are a heterogeneous population of innate lymphocytes whose potent anticancer properties make them ideal candidates for cellular therapeutic application. However, our lack of understanding of the role of NK cell diversity in antitumor responses has hindered advances in this area. In this study, we describe a new CD56dim NK cell subset characterized by the lack of expression of DNAX accessory molecule-1 (DNAM-1). Compared with CD56bright and CD56dimDNAM-1pos NK cell subsets, CD56dimDNAM-1neg NK cells displayed reduced motility, poor proliferation, lower production of interferon-γ, and limited killing capacities. Soluble factors secreted by CD56dimDNAM-1neg NK cells impaired CD56dimDNAM-1pos NK cell-mediated killing, indicating a potential inhibitory role for the CD56dimDNAM-1neg NK cell subset. Transcriptome analysis revealed that CD56dimDNAM-1neg NK cells constitute a new mature NK cell subset with a specific gene signature. Upon in vitro cytokine stimulation, CD56dimDNAM-1neg NK cells were found to differentiate from CD56dimDNAM-1pos NK cells. Finally, we report a dysregulation of NK cell subsets in the blood of patients diagnosed with Hodgkin lymphoma and diffuse large B-cell lymphoma, characterized by decreased CD56dimDNAM-1pos/CD56dimDNAM-1neg NK cell ratios and reduced cytotoxic activity of CD56dimDNAM-1pos NK cells. Altogether, our data offer a better understanding of human peripheral blood NK cell populations and have important clinical implications for the design of NK cell-targeting therapies.
| S-EPMC6560343 | biostudies-literature
Project description:IntroductionThe transcription factor HELIOS is primarily known for its expression in CD4 regulatory T cells, both in humans and mice. In mice, HELIOS is found in exhausted CD8 T cells. However, information on human HELIOS+ CD8 T cells is limited and conflicting.MethodsIn this study, we characterized by flow cytometry and transcriptomic analyses human HELIOS+ CD8 T cells.ResultsThese T cells primarily consist of memory cells and constitute approximately 21% of blood CD8 T cells. In comparison with memory HELIOS- T-BEThigh CD8 T cells that displayed robust effector functions, the memory HELIOS+ T-BEThigh CD8 T cells produce lower amounts of IFN-γ and TNF-α and have a lower cytotoxic potential. We wondered if these cells participate in the immune response against viral antigens, but did not find HELIOS+ cells among CD8 T cells recognizing CMV peptides presented by HLA-A2 and HLA-B7. However, we found HELIOS+ CD8 T cells that recognize a CMV peptide presented by MHC class Ib molecule HLA-E. Additionally, a portion of HELIOS+ CD8 T cells is characterized by the expression of CD161, often used as a surface marker for identifying TC17 cells. These CD8 T cells express TH17/TC17-related genes encoding RORgt, RORa, PLZF, and CCL20.DiscussionOur findings emphasize that HELIOS is expressed across various CD8 T cell populations, highlighting its significance beyond its role as a transcription factor for Treg or exhausted murine CD8 T cells. The significance of the connection between HELIOS and HLA-E restriction is yet to be understood.
| S-EPMC10770868 | biostudies-literature