bims-imseme 2023-03-26 papers

bims-imseme

Biomed News

on Immunosenescence and T cell metabolism

Issue of 2023‒03‒26
fourteen papers selected by
Pierpaolo Ginefra
Ludwig Institute for Cancer Research

The lactate dehydrogenase (LDH) isoenzyme spectrum enables optimally controlling T cell glycolysis and differentiation.
The degree of T cell stemness differentially impacts the potency of adoptive cancer immunotherapy in a Lef-1 and Tcf-1 dependent manner.
Heterozygous OT-I mice reveal that antigen-specific CD8+ T cells shift from apoptotic to necrotic killers in the elderly.
Hypoxia induces dichotomous and reversible attenuation of T cell responses through reactive oxygen species-dependent phenotype redistribution and delay in lymphoblast proliferation.
An atlas of gene regulatory networks for T memory cells in youth and old age.
Immunometabolism at the crossroads of obesity and cancer-a Keystone Symposia report.
T-cell exhaustion in CAR-T-cell therapy and strategies to overcome it.
Indoleamine 2,3-dioxygenase 1 in circumventing checkpoint inhibitor responses: Updated.
Aiolos represses CD4+ T cell cytotoxic programming via reciprocal regulation of TFH transcription factors and IL-2 sensitivity.
Loss of CD28 expression associates with severe T-cell exhaustion in acute myeloid leukemia.
Saturated fatty acids dampen the immunogenicity of cancer by suppressing STING.
Stepwise activities of mSWI/SNF family chromatin remodeling complexes direct T cell activation and exhaustion.
Clonal haematopoiesis and dysregulation of the immune system.
Regulation and Immunotherapeutic Targeting of the Epigenome in Exhausted CD8 T Cell Responses.

Sci Adv. 2023 Mar 24. 9(12): eadd9554

The lactate dehydrogenase (LDH) isoenzyme spectrum enables optimally controlling T cell glycolysis and differentiation.

Xuyong Chen, Lingling Liu, Siwen Kang, Jn Rashida Gnanaprakasam, Ruoning Wang.

Isoenzyme divergence is a prevalent mechanism governing tissue-specific and developmental stage-specific metabolism in mammals. The lactate dehydrogenase (LDH) isoenzyme spectrum reflects the tissue-specific metabolic status. We found that three tetrameric isoenzymes composed of LDHA and LDHB (LDH-3/4/5) comprise the LDH spectrum in T cells. Genetically deleting LDHA or LDHB altered the isoenzyme spectrum by removing all heterotetramers and leaving T cells with LDH-1 (the homotetramer of LDHB) or LDH-5 (the homotetramer of LDHA), respectively. Accordingly, deleting LDHA suppressed glycolysis, cell proliferation, and differentiation. Unexpectedly, deleting LDHB enhanced glycolysis but suppressed T cell differentiation, indicating that an optimal zone of glycolytic activity is required to maintain cell fitness. Mechanistically, the LDH isoenzyme spectrum imposed by LDHA and LDHB is necessary to optimize glycolysis to maintain a balanced nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide hydrogen pool. Our results suggest that the LDH isoenzyme spectrum enables "Goldilocks levels" of glycolytic and redox activity to control T cell differentiation.

DOI: https://doi.org/10.1126/sciadv.add9554
bioRxiv. 2023 Mar 10. pii: 2023.03.08.531589. [Epub ahead of print]

The degree of T cell stemness differentially impacts the potency of adoptive cancer immunotherapy in a Lef-1 and Tcf-1 dependent manner.

Guillermo O Rangel Rivera, Connor J Dwyer, Hannah M Knochelmann, Aubrey S Smith, Arman Aksoy, Anna C Cole, Megan M Wyatt, Jessica E Thaxton, Gregory B Lesinski, Chrystal M Paulos.

Generating stem memory T cells (T SCM ) is a key goal for improving cancer immunotherapy. Yet, the optimal way to modulate signaling pathways that enrich T SCM properties remains elusive. Here, we discovered that the degree to which the PI3Kδ pathway is blocked pharmaceutically can generate T cells with differential levels of stemness properties. This observation was based on the progressive enrichment of transcriptional factors of stemness (Tcf-1 and Lef-1). Additional investigation revealed that T cells with high stemness features had enhanced metabolic plasticity, marked by heightened mitochondrial function and glucose uptake. Conversely, T cells with low or medium features of stemness expressed more inhibitory checkpoint receptors (Tim-3, CD39) and were vulnerable to antigen-induced cell death. Only TCR-antigen specific T cells with high stemness persisted following adoptive transfer in vivo and mounted protective immunity to melanoma tumors. Likewise, the strongest level of PI3Kδ blockade in vitro generated human tumor infiltrating lymphocytes (TILs) and CAR T cells with heightened stemness properties, in turn bolstering their capacity to regress human mesothelioma tumors. We find that the level of stemness T cells possess in vitro differentially impacts their potency upon transfer in three tumor models. Mechanistically, both Lef-1 and Tcf-1 sustain anti-tumor protection by high T SCM , as deletion of either one compromised cellular therapy. Collectively, these findings highlight the therapeutic potential of carefully modulating PI3Kδ signaling in T cells to confer high stemness and mediate protective responses to solid tumors.

DOI: https://doi.org/10.1101/2023.03.08.531589
Aging Cell. 2023 Mar 22. e13824

Heterozygous OT-I mice reveal that antigen-specific CD8+ T cells shift from apoptotic to necrotic killers in the elderly.

Dorina Zöphel, Lea Kaschek, Romy Steiner, Sandra Janku, Hsin-Fang Chang, Annette Lis.

  Numerous alterations in CD8+ T cells contribute to impaired immune responses in elderly individuals. However, the discrimination between cell-intrinsic dysfunctions and microenvironmental changes is challenging. TCR transgenic OT-I mice are utilized to investigate CD8+ T-cell immunity, but their immunodeficient phenotype hampers their use especially in aging. Here, we demonstrate that using a heterozygous OT-I model minimizes the current limitations and provides a valuable tool to assess antigen-specific T-cell responses even at old age. We analyzed phenotypic and functional characteristics of CD8+ T cells from OT-I+/+ and OT-I+/- mice to prove the applicability of the heterozygous system. Our data reveal that OVA-activated CD8+ T cells from adult OT-I+/- mice proliferate, differentiate, and exert cytolytic activity equally to their homozygous counterparts. Moreover, common age-related alterations in CD8+ T cells, including naive T-cell deterioration and decreased proliferative capacity, also occur in elderly OT-I+/- mice, indicating the wide range of applications for in vivo and in vitro aging studies. We used the OT-I+/- model to investigate cell-intrinsic alterations affecting the cytotoxic behavior of aged CD8+ T cells after antigen-specific in vitro activation. Time-resolved analysis of antigen-directed target cell lysis confirmed previous observations that the cytotoxic capacity of CD8+ T cells increases with age. Surprisingly, detailed single cell analysis revealed that transcriptional upregulation of perforin in aged CD8+ T cells shifts the mode of target cell death from granzyme-mediated apoptosis to rapid induction of necrosis. This unexpected capability might be beneficial or detrimental for the aging host and requires detailed evaluation.

Keywords:  CD8+ T cells; OT-I; adaptive immunity; aging; apoptosis; cytotoxicity; necrosis; perforin

DOI:  https://doi.org/10.1111/acel.13824
Free Radic Res. 2023 Mar 22. 1-13

Hypoxia induces dichotomous and reversible attenuation of T cell responses through reactive oxygen species-dependent phenotype redistribution and delay in lymphoblast proliferation.

Dharmendra Kumar Maurya, Deepak Sharma, Santosh Kumar Sandur.

  As T cells transit between blood, lymphoid organs, and peripheral tissues, they experience varied levels of oxygen/hypoxia in inflamed tissues, skin, intestinal lining, and secondary lymphoid organs. Critical illness among COVID-19 patients is also associated with transient hypoxia and attenuation of T cell responses. Hypoxia is the fulcrum of altered metabolism, impaired functions, and cessation of growth of a subset of T cells. However, the restoration of normal T cell functions following transient hypoxia and kinetics of their phenotype-redistribution is not completely understood. Here, we sought to understand kinetics and reversibility of dichotomous T cell responses under sustained and transient hypoxia. We found that a subset of activated T cells accumulated as lymphoblasts under hypoxia. Further, T cells showed the normal expression of activation markers CD25 and CD69 and inflammatory cytokine secretion but a subset exhibited delayed cell proliferation under hypoxia. Increased levels of reactive oxygen species (ROS) in cytosol and mitochondria were seen during dichotomous and reversible attenuation of T cell response under hypoxia. Cell cycle analysis revealed maximum levels of cytosolic and mitochondrial ROS in dividing T cells (in S, G2, or M phase). Hypoxic T cells also showed specific attenuation of activation induced memory phenotype conversion without affecting naïve and activated T cells. Hypoxia-related attenuation of T cell proliferation was also found to be reversible in an allogeneic leukocyte specific mixed lymphocyte reaction assay. In summary, our results show that hypoxia induces a reversible delay in proliferation of a subset of T cells which is associated with obliteration of memory phenotype and specific increase in cytosolic/mitochondrial ROS levels in actively dividing subpopulation. Thus, the transient reoxygenation of hypoxic patients may restore normal T cell responses.

Keywords:  Hypoxia; T cell resilience; cell cycle; homeostatic proliferation; mixed lymphocyte reaction; reactive oxygen species

DOI:  https://doi.org/10.1080/10715762.2023.2178918
bioRxiv. 2023 Mar 10. pii: 2023.03.07.531590. [Epub ahead of print]

An atlas of gene regulatory networks for T memory cells in youth and old age.

Joseph A Wayman, Alyssa Thomas, Anthony Bejjani, Alexander Katko, Maha Almanan, Alzbeta Godarova, Svetlana Korinfskaya, Tareian A Cazares, Masashi Yukawa, Leah C Kottyan, Artem Barski, Claire A Chougnet, David A Hildeman, Emily R Miraldi.

Aging profoundly affects immune system function, rendering the elderly more susceptible to pathogens, cancers and chronic inflammation. We previously identified a population of IL-10- producing, T follicular helper-like cells (" Tfh10 "), linked to suppressed vaccine responses in aged mice. Here, we use the power of single-cell ( sc )genomics and genome-scale modeling to characterize Tfh10 - and the full CD4 + memory T cell ( CD4 + TM ) compartment - in young and old mice. Unprecedented scRNA-seq coverage of the CD4 + TM compartment and parallel chromatin accessibility measurements (scATAC-seq) enabled identification of 13 CD4 + TM populations, which we validated as a reference through comprehensive cross-comparison to aging cell atlases and scRNA-seq studies reporting Tfh10 in other contexts. Beyond robust characterization of age- and cell-type-dependent transcriptional landscapes, we used integrative computational modeling to predict the underlying regulatory mechanisms: We inferred gene regulatory networks ( GRNs ) that describe transcription-factor control of gene expression in each T-cell population and how these circuits change with age. Furthermore, we integrated our data with prior, pan-cell scRNA- seq studies to identify intercellular-signaling networks driving age-dependent changes in CD4 + TM. Our atlas of finely resolved CD4 + TM subsets, GRNs and cell-cell communication networks is a critical resource for analysis of biologic processes operative in memory T cells in youth and old age. The resource presents new opportunities to manipulate regulatory circuits in CD4 + TM, which, long-term, could improve immune responses in the elderly.

DOI: https://doi.org/10.1101/2023.03.07.531590
Ann N Y Acad Sci. 2023 Mar 24.

Immunometabolism at the crossroads of obesity and cancer-a Keystone Symposia report.

Jennifer Cable, Jeffrey C Rathmell, Erika L Pearce, Ping-Chih Ho, Marcia C Haigis, Murad R Mamedov, Meng-Ju Wu, Susan M Kaech, Lydia Lynch, Mark A Febbraio, Sagar P Bapat, Hanna S Hong, Weiping Zou, Yasmine Belkaid, Zuri A Sullivan, Andrea Keller, Stefanie K Wculek, Douglas R Green, Catherine Postic, Ido Amit, Salvador Aznar Benitah, Russell G Jones, Miguel Reina-Campos, Santiago Valle Torres, Semir Beyaz, Donal Brennan, Luke A J O'Neill, Rachel J Perry, Dirk Brenner.

  Immunometabolism considers the relationship between metabolism and immunity. Typically, researchers focus on either the metabolic pathways within immune cells that affect their function or the impact of immune cells on systemic metabolism. A more holistic approach that considers both these viewpoints is needed. On September 5-8, 2022, experts in the field of immunometabolism met for the Keystone symposium "Immunometabolism at the Crossroads of Obesity and Cancer" to present recent research across the field of immunometabolism, with the setting of obesity and cancer as an ideal example of the complex interplay between metabolism, immunity, and cancer. Speakers highlighted new insights on the metabolic links between tumor cells and immune cells, with a focus on leveraging unique metabolic vulnerabilities of different cell types in the tumor microenvironment as therapeutic targets and demonstrated the effects of diet, the microbiome, and obesity on immune system function and cancer pathogenesis and therapy. Finally, speakers presented new technologies to interrogate the immune system and uncover novel metabolic pathways important for immunity.

Keywords:  cancer; immunity; immunometabolism; immunotherapy; metabolism; obesity

DOI:  https://doi.org/10.1111/nyas.14976
Immunology. 2023 Mar 20.

T-cell exhaustion in CAR-T-cell therapy and strategies to overcome it.

Xuechen Yin, Lingfeng He, Zhigang Guo.

  Tumour immunotherapy has achieved good therapeutic effects in clinical practice and has received increased attention. Cytotoxic T cells undoubtedly play an important role in tumour immunotherapy. As a revolutionary tumour immunotherapy approach, chimeric antigen receptor T-cell (CAR-T-cell) therapy has made breakthroughs in the treatment of haematological cancers. However, T cells are easily exhausted in vivo, especially after they enter solid tumours. The exhaustion of T cells can lead to poor results of CAR-T-cell therapy in the treatment of solid tumours. Here, we review the reasons for T-cell exhaustion and how T-cell exhaustion develops. We also review and discuss ways to improve CAR-T-cell therapy effects by regulating T-cell exhaustion.

Keywords:  CAR-T-cell therapy; T-cell exhaustion; immunotherapy

DOI:  https://doi.org/10.1111/imm.13642
Int Immunopharmacol. 2023 Mar 16. pii: S1567-5769(23)00353-3. [Epub ahead of print]118 110032

Indoleamine 2,3-dioxygenase 1 in circumventing checkpoint inhibitor responses: Updated.

Arian Charehjoo, Jamal Majidpoor, Keywan Mortezaee.

  Metabolic alterations occur commonly in tumor cells as a way to adapt available energetic sources for their proliferation, survival and resistance. Indoleamine 2,3-dioxygenase 1 (IDO1) is an intracellular enzyme catalyzing tryptophan degradation into kynurenine. IDO1 expression shows a rise in the stroma of many types of human cancers, and it provides a negative feedback mechanism for cancer evasion from immunosurveillance. Upregulation of IDO1 correlates with cancer aggression, poor prognosis and shortened patient survival. The increased activity of this endogenous checkpoint impairs effector T cell function, increases regulatory T cell (Treg) population and induces immune tolerance, so its inhibition potentiates anti-tumor immune responses and reshapes immunogenic state of tumor microenvironment (TME) presumably through normalizing effector T cell activity. A point is that the expression of this immunoregulatory marker is upregulated after immune checkpoint inhibitor (ICI) therapy, and that it has inducible effect on expression of other checkpoints. These are indicative of the importance of IDO1 as an attractive immunotherapeutic target and rationalizing combination of IDO1 inhibitors with ICI drugs in patients with advanced solid cancers. In this review, we aimed to discuss about the impact of IDO1 on tumor immune ecosystem, and the IDO1-mediated bypass of ICI therapy. The efficacy of IDO1 inhibitor therapy in combination with ICIs in advanced/metastatic solid tumors is also a focus of this paper.

Keywords:  3-dioxygenase 1 (IDO1); Aryl hydrocarbon receptor (AHR); Cytotoxic T lymphocyte associated antigen-4 (CTLA-4); Epacadostat; Immune checkpoint inhibitor (ICI); Indoleamine 2; Programmed death-1 (PD-1); Programmed death-ligand 1 (PD-L1); Tumor microenvironment (TME)

DOI:  https://doi.org/10.1016/j.intimp.2023.110032
Nat Commun. 2023 Mar 24. 14(1): 1652

Aiolos represses CD4+ T cell cytotoxic programming via reciprocal regulation of TFH transcription factors and IL-2 sensitivity.

Kaitlin A Read, Devin M Jones, Srijana Pokhrel, Emily D S Hales, Aditi Varkey, Jasmine A Tuazon, Caprice D Eisele, Omar Abdouni, Abbey Saadey, Melissa R Leonard, Robert T Warren, Michael D Powell, Jeremy M Boss, Emily A Hemann, Jacob S Yount, Gang Xin, Hazem E Ghoneim, Chan-Wang J Lio, Aharon G Freud, Patrick L Collins, Kenneth J Oestreich.

During intracellular infection, T follicular helper (TFH) and T helper 1 (TH1) cells promote humoral and cell-mediated responses, respectively. Another subset, CD4-cytotoxic T lymphocytes (CD4-CTLs), eliminate infected cells via functions typically associated with CD8+ T cells. The mechanisms underlying differentiation of these populations are incompletely understood. Here, we identify the transcription factor Aiolos as a reciprocal regulator of TFH and CD4-CTL programming. We find that Aiolos deficiency results in downregulation of key TFH transcription factors, and consequently reduced TFH differentiation and antibody production, during influenza virus infection. Conversely, CD4-CTL programming is elevated, including enhanced Eomes and cytolytic molecule expression. We further demonstrate that Aiolos deficiency allows for enhanced IL-2 sensitivity and increased STAT5 association with CD4-CTL gene targets, including Eomes, effector molecules, and IL2Ra. Thus, our collective findings identify Aiolos as a pivotal regulator of CD4-CTL and TFH programming and highlight its potential as a target for manipulating CD4+ T cell responses.

DOI: https://doi.org/10.1038/s41467-023-37420-0
Front Immunol. 2023 ;14 1139517

Loss of CD28 expression associates with severe T-cell exhaustion in acute myeloid leukemia.

Yueting Huang, Huijian Zheng, Yuwen Zhu, Yan Hong, Jie Zha, Zhijuan Lin, Zhifeng Li, Caiyan Wang, Zhihong Fang, Xingxing Yu, Long Liu, Bing Xu.

  Introduction: Despite accumulated evidence in T-cell exhaustion in acute myeloid leukemia (AML), the immunotherapeutic targeting exhausted T cells such as programmed cell death protein 1 (PD-1) blockade in AML failed to achieve satisfying efficacy. Characteristics of exhausted T cells in AML remained to be explored.Methods: Phenotypic analysis of T cells in bone marrow (BM) using flow cytometry combining senescent and exhausted markers was performed in de novo AML patients and healthy donors as well as AML patients with complete remission (CR). Functional analysis of T-cell subsets was also performed in de novo AML patients using flow cytometry.
Results: T cells experienced a phenotypic shift to terminal differentiation characterized by increased loss of CD28 expression and decrease of naïve T cells. Additionally, lack of CD28 expression could help define a severely exhausted subset from generally exhausted T cells (PD-1+TIGIT+). Moreover, CD28- subsets rather than CD28+ subsets predominantly contributed to the significant accumulation of PD-1+TIGIT+ T cells in AML patients. Further comparison of de novo and CR AML patients showed that T-cell exhaustion status was improved after disease remission, especially in CD28+ subsets. Notably, higher frequency of CD28-TIGIT-CD4+ T cells correlated with the presence of minimal residual disease in AML-CR group. However, the correlation between CD28- exhausted T cells and cytogenetic risk or white blood cell count was not observed, except for that CD28- exhausted CD4+ T cells correlated with lymphocyte counts. Intriguingly, larger amount of CD28-TGITI+CD8+ T cells at diagnosis was associated with poor treatment response and shorter leukemia free survival.
Discussion: In summary, lack of CD28 expression defined a severely exhausted status from exhausted T cells. Accumulation of CD28- exhausted T cells was linked to occurrence of AML, and correlated to poor clinical outcome. Our data might facilitate the development of combinatory strategies to improve the efficacy of PD-1 blockade in AML.

Keywords:  CD28; T cell; acute myeloid leukemia; exhaustion; senescence

DOI:  https://doi.org/10.3389/fimmu.2023.1139517
Cell Rep. 2023 Mar 22. pii: S2211-1247(23)00314-5. [Epub ahead of print]42(4): 112303

Saturated fatty acids dampen the immunogenicity of cancer by suppressing STING.

Blake R Heath, Wang Gong, Hülya F Taner, Luke Broses, Kohei Okuyama, Wanqing Cheng, Max Jin, Zackary R Fitzsimonds, Andriana Manousidaki, Yuesong Wu, Shaoping Zhang, Haitao Wen, Steven B Chinn, Eric Bartee, Yuying Xie, James J Moon, Yu Leo Lei.

  Oncogenes destabilize STING in epithelial cell-derived cancer cells, such as head and neck squamous cell carcinomas (HNSCCs), to promote immune escape. Despite the abundance of tumor-infiltrating myeloid cells, HNSCC presents notable resistance to STING stimulation. Here, we show how saturated fatty acids in the microenvironment dampen tumor response to STING stimulation. Using single-cell analysis, we found that obesity creates an IFN-I-deprived tumor microenvironment with a massive expansion of suppressive myeloid cell clusters and contraction of effector T cells. Saturated fatty acids, but not unsaturated fatty acids, potently inhibit the STING-IFN-I pathway in HNSCC cells. Myeloid cells from obese mice show dampened responses to STING stimulation and are more suppressive of T cell activation. In agreement, obese hosts exhibited increased tumor burden and lower responsiveness to STING agonist. As a mechanism, saturated fatty acids induce the expression of NLRC3, depletion of which results in a T cell inflamed tumor microenvironment and IFN-I-dependent tumor control.

Keywords:  CP: Cancer; CP: Immunology; NLRC3; STING; head and neck cancer; immunogenicity; innate immunity; metabolism; obesity; saturated fatty acids; type-I interferon

DOI:  https://doi.org/10.1016/j.celrep.2023.112303
Mol Cell. 2023 Mar 15. pii: S1097-2765(23)00153-3. [Epub ahead of print]

Stepwise activities of mSWI/SNF family chromatin remodeling complexes direct T cell activation and exhaustion.

Elena Battistello, Kimberlee A Hixon, Dawn E Comstock, Clayton K Collings, Xufeng Chen, Javier Rodriguez Hernaez, Soobeom Lee, Kasey S Cervantes, Madeline M Hinkley, Konstantinos Ntatsoulis, Annamaria Cesarano, Kathryn Hockemeyer, W Nicholas Haining, Matthew T Witkowski, Jun Qi, Aristotelis Tsirigos, Fabiana Perna, Iannis Aifantis, Cigall Kadoch.

  Highly coordinated changes in gene expression underlie T cell activation and exhaustion. However, the mechanisms by which such programs are regulated and how these may be targeted for therapeutic benefit remain poorly understood. Here, we comprehensively profile the genomic occupancy of mSWI/SNF chromatin remodeling complexes throughout acute and chronic T cell stimulation, finding that stepwise changes in localization over transcription factor binding sites direct site-specific chromatin accessibility and gene activation leading to distinct phenotypes. Notably, perturbation of mSWI/SNF complexes using genetic and clinically relevant chemical strategies enhances the persistence of T cells with attenuated exhaustion hallmarks and increased memory features in vitro and in vivo. Finally, pharmacologic mSWI/SNF inhibition improves CAR-T expansion and results in improved anti-tumor control in vivo. These findings reveal the central role of mSWI/SNF complexes in the coordination of T cell activation and exhaustion and nominate small-molecule-based strategies for the improvement of current immunotherapy protocols.

Keywords:  ATP-dependent chromatin remodeling; CRISPR screening; CUT&Tag; HNF1B; PROTACs; SWI/SNF; T cells; immunotherapy; small-molecule inhibitors; transcription factors

DOI:  https://doi.org/10.1016/j.molcel.2023.02.026
Nat Rev Immunol. 2023 Mar 20.

Clonal haematopoiesis and dysregulation of the immune system.

Roger Belizaire, Waihay J Wong, Michelle L Robinette, Benjamin L Ebert.

Age-related diseases are frequently linked to pathological immune dysfunction, including excessive inflammation, autoreactivity and immunodeficiency. Recent analyses of human genetic data have revealed that somatic mutations and mosaic chromosomal alterations in blood cells - a condition known as clonal haematopoiesis (CH) - are associated with ageing and pathological immune dysfunction. Indeed, large-scale epidemiological studies and experimental mouse models have demonstrated that CH can promote cardiovascular disease, chronic obstructive pulmonary disease, chronic liver disease, osteoporosis and gout. The genes most frequently mutated in CH, the epigenetic regulators TET2 and DNMT3A, implicate increased chemokine expression and inflammasome hyperactivation in myeloid cells as a possible mechanistic connection between CH and age-related diseases. In addition, TET2 and DNMT3A mutations in lymphoid cells have been shown to drive methylation-dependent alterations in differentiation and function. Here we review the observational and mechanistic studies describing the connection between CH and pathological immune dysfunction, the effects of CH-associated genetic alterations on the function of myeloid and lymphoid cells, and the clinical and therapeutic implications of CH as a target for immunomodulation.

DOI: https://doi.org/10.1038/s41577-023-00843-3
J Immunol. 2023 Apr 01. 210(7): 869-879

Regulation and Immunotherapeutic Targeting of the Epigenome in Exhausted CD8 T Cell Responses.

B Rhodes Ford, Amanda C Poholek.

Exhaustion is a state of CD8 T cell differentiation that occurs in settings of chronic Ag such as tumors, chronic viral infection, and autoimmunity. Cellular differentiation is driven by a series of environmental signals that promote epigenetic landscapes that set transcriptomes needed for function. For CD8 T cells, the epigenome that underlies exhaustion is distinct from effector and memory cell differentiation, suggesting that signals early on set in motion a process where the epigenome is modified to promote a trajectory toward a dysfunctional state. Although we know many signals that promote exhaustion, putting this in the context of the epigenetic changes that occur during differentiation has been less clear. In this review, we aim to summarize the epigenetic changes associated with exhaustion in the context of signals that promote it, highlighting immunotherapeutic studies that support these observations or areas for future therapeutic opportunities.

DOI: https://doi.org/10.4049/jimmunol.2200681