IKAROS Family Transcription Factors in Lymphocyte Differentiation and Function.

The IKAROS family of transcription factors comprises four zinc-finger proteins (IKAROS, HELIOS, AIOLOS, and EOS), which over the last decades have been established to be critical regulators of the development and function of lymphoid cells. These factors act as homo- or heterodimers and are involved both in gene activation and repression. Their function often involves cross-talk with other regulatory circuits, such as the JAK/STAT, NF-κB, and NOTCH pathways. They control lymphocyte differentiation at multiple stages and are notably critical for lymphoid commitment in multipotent hematopoietic progenitors and for T and B cell differentiation downstream of pre-TCR and pre-BCR signaling. They also control many aspects of effector functions in mature B and T cells. They are dysregulated or mutated in multiple pathologies affecting the lymphoid system, which range from leukemia to immunodeficiencies. In this chapter, we review the molecular and physiological function of these factors in lymphocytes and their implications in human pathologies.

Structural properties of glucan from Russula griseocarnosa and its immunomodulatory activities mediated via T cell differentiation.

The polysaccharide, RGP2, was isolated from Russula griseocarnosa and its immunostimulatory effects were confirmed in cyclophosphamide (CTX)-induced immunosuppressed mice. Following purification via chromatography, structural analysis revealed that RGP2 had a molecular weight of 11.82 kDa and consisted of glucose (Glc), galactose (Gal), mannose, glucuronic acid and glucosamine. Bond structure analysis and nuclear magnetic resonance characterization confirmed that the main chain of RGP2 was formed by →6)-ß-D-Glcp-(1→, →3)-ß-D-Glcp-(1→ and →6)-α-D-Galp-(1→, which was substituted at O-3 of →6)-ß-D-Glcp-(1→ by ß-D-Glcp-(1→. RGP2 was found to ameliorate pathological damage in the spleen and enhance immune cell activity in immunosuppressed mice. Based on combined multiomics analysis, RGP2 altered the abundance of immune-related microbiota (such as Lactobacillus, Faecalibacterium, and Bacteroides) in the gut and metabolites (uridine, leucine, and tryptophan) in the serum. Compared with immunosuppressed mice, RGP2 also restored the function of antigen-presenting cells, promoted the polarization of macrophages into the M1 phenotype, positively affected the differentiation of helper T cells, and inhibited regulatory T cell differentiation through the protein kinase B (AKT)/mechanistic target of rapamycin (mTOR) pathway, ultimately exerting an immune boosting function. Overall, our findings highlight therapeutic strategies to alleviate CTX-induced immunosuppression in a clinical setting.

Trichinella spiralis Paramyosin Alleviates Collagen-Induced Arthritis in Mice by Modulating CD4+ T Cell Differentiation.

Rheumatoid arthritis (RA) is an autoimmune disease that significantly impacts quality of life by disrupting CD4+ T cell immune homeostasis. The identification of a low-side-effect drug for RA treatment is urgently needed. Our previous study suggests that Trichinella spiralis paramyosin (Ts-Pmy) has immunomodulatory effects, but its potential effect on CD4+ T cell response in RA remains unclear. In this study, we used a murine model to investigate the role of rTs-Pmy in regulating CD4+ T cell differentiation in collagen-induced arthritis (CIA). Additionally, we assessed the impact of rTs-Pmy on CD4+ T cell differentiation towards the Th1 and Th17 phenotypes, which are associated with inflammatory responses in arthritis, using in vitro assays. The results demonstrated that rTs-Pmy administration reduced arthritis severity by inhibiting Th1 and Th17 response while enhancing Treg response. Prophylactic administration of Ts-Pmy showed superior efficacy on CIA compared to therapeutic administration. Furthermore, in vitro assays demonstrated that rTs-Pmy could inhibit the differentiation of CD4+ T cells into Th1 and Th17 while inducing the production of Tregs, suggesting a potential mechanism underlying its therapeutic effects. This study suggests that Ts-Pmy may ameliorate CIA by restoring the immune balance of CD4+ T cells and provides new insights into the mechanism through which helminth-derived proteins exert their effects on autoimmune diseases.

Plasmodium infection induces phenotypic, clonal, and spatial diversity among differentiating CD4+ T cells.

Naive CD4+ T cells must differentiate in order to orchestrate immunity to Plasmodium, yet understanding of their emerging phenotypes, clonality, spatial distributions, and cellular interactions remains incomplete. Here, we observe that splenic polyclonal CD4+ T cells differentiate toward T helper 1 (Th1) and T follicular helper (Tfh)-like states and exhibit rarer phenotypes not elicited among T cell receptor (TCR) transgenic counterparts. TCR clones present at higher frequencies exhibit Th1 skewing, suggesting that variation in major histocompatibility complex class II (MHC-II) interaction influences proliferation and Th1 differentiation. To characterize CD4+ T cell interactions, we map splenic microarchitecture, cellular locations, and molecular interactions using spatial transcriptomics at near single-cell resolution. Tfh-like cells co-locate with stromal cells in B cell follicles, while Th1 cells in red pulp co-locate with activated monocytes expressing multiple chemokines and MHC-II. Spatial mapping of individual transcriptomes suggests that proximity to chemokine-expressing monocytes correlates with stronger effector phenotypes in Th1 cells. Finally, CRISPR-Cas9 gene disruption reveals a role for CCR5 in promoting clonal expansion and Th1 differentiation. A database of cellular locations and interactions is presented: https://haquelab.mdhs.unimelb.edu.au/spatial_gui/.

CXCL16-dependent scavenging of oxidized lipids by islet macrophages promotes differentiation of pathogenic CD8+ T cells in diabetic autoimmunity.

The pancreatic islet microenvironment is highly oxidative, rendering ß cells vulnerable to autoinflammatory insults. Here, we examined the role of islet resident macrophages in the autoimmune attack that initiates type 1 diabetes. Islet macrophages highly expressed CXCL16, a chemokine and scavenger receptor for oxidized low-density lipoproteins (OxLDLs), regardless of autoimmune predisposition. Deletion of Cxcl16 in nonobese diabetic (NOD) mice suppressed the development of autoimmune diabetes. Mechanistically, Cxcl16 deficiency impaired clearance of OxLDL by islet macrophages, leading to OxLDL accumulation in pancreatic islets and a substantial reduction in intra-islet transitory (Texint) CD8+ T cells displaying proliferative and effector signatures. Texint cells were vulnerable to oxidative stress and diminished by ferroptosis; PD-1 blockade rescued this population and reversed diabetes resistance in NOD.Cxcl16-/- mice. Thus, OxLDL scavenging in pancreatic islets inadvertently promotes differentiation of pathogenic CD8+ T cells, presenting a paradigm wherein tissue homeostasis processes can facilitate autoimmune pathogenesis in predisposed individuals.

Immunometabolism of CD8+ T cell differentiation in cancer.

CD8+ cytotoxic T lymphocytes (CTLs) are central mediators of tumor immunity and immunotherapies. Upon tumor antigen recognition, CTLs differentiate from naive/memory-like toward terminally exhausted populations with more limited function against tumors. Such differentiation is regulated by both immune signals, including T cell receptors (TCRs), co-stimulation, and cytokines, and metabolism-associated processes. These immune signals shape the metabolic landscape via signaling, transcriptional and post-transcriptional mechanisms, while metabolic processes in turn exert spatiotemporal effects to modulate the strength and duration of immune signaling. Here, we review the bidirectional regulation between immune signals and metabolic processes, including nutrient uptake and intracellular metabolic pathways, in shaping CTL differentiation and exhaustion. We also discuss the mechanisms underlying how specific nutrient sources and metabolite-mediated signaling events orchestrate CTL biology. Understanding how metabolic programs and their interplay with immune signals instruct CTL differentiation and exhaustion is crucial to uncover tumor-immune interactions and design novel immunotherapies.

Construction of ceRNA regulatory networks for active pulmonary tuberculosis.

Delayed diagnosis in patients with pulmonary tuberculosis (PTB) often leads to serious public health problems. High throughput sequencing was used to determine the expression levels of lncRNAs, mRNAs, and miRNAs in the lesions and adjacent health lung tissues of patients with PTB. Their differential expression profiles between the two groups were compared, and 146 DElncRs, 447 DEmRs, and 29 DEmiRs were obtained between lesions and adjacent health tissues in patients with PTB. Enrichment analysis for mRNAs showed that they were mainly involved in Th1, Th2, and Th17 cell differentiation. The lncRNAs, mRNAs with target relationship with miRNAs were predicted respectively, and correlation analysis was performed. The ceRNA regulatory network was obtained by comparing with the differentially expressed transcripts (DElncRs, DEmRs, DEmiRs), then 2 lncRNAs mediated ceRNA networks were established. The expression of genes within the network was verified by quantitative real-time PCR (qRT-PCR). Flow cytometric analysis revealed that the proportion of Th1 cells and Th17 cells was lower in PTB than in controls, while the proportion of Th2 cells increased. Our results provide rich transcriptome data for a deeper investigation of PTB. The ceRNA regulatory network we obtained may be instructive for the diagnosis and treatment of PTB.

Cellular metabolism regulates the differentiation and function of T-cell subsets.

T cells are an important component of adaptive immunity and protect the host from infectious diseases and cancers. However, uncontrolled T cell immunity may cause autoimmune disorders. In both situations, antigen-specific T cells undergo clonal expansion upon the engagement and activation of antigens. Cellular metabolism is reprogrammed to meet the increase in bioenergetic and biosynthetic demands associated with effector T cell expansion. Metabolites not only serve as building blocks or energy sources to fuel cell growth and expansion but also regulate a broad spectrum of cellular signals that instruct the differentiation of multiple T cell subsets. The realm of immunometabolism research is undergoing swift advancements. Encapsulating all the recent progress within this concise review in not possible. Instead, our objective is to provide a succinct introduction to this swiftly progressing research, concentrating on the metabolic intricacies of three pivotal nutrient classes-lipids, glucose, and amino acids-in T cells. We shed light on recent investigations elucidating the roles of these three groups of metabolites in mediating the metabolic and immune functions of T cells. Moreover, we delve into the prospect of "editing" metabolic pathways within T cells using pharmacological or genetic approaches, with the aim of synergizing this approach with existing immunotherapies and enhancing the efficacy of antitumor and antiinfection immune responses.

Effective and stable gene transduction in rhesus macaque iPSCs capable of T-lineage differentiation utilizing the piggyBac system.

Introduction: Genetically modified human induced pluripotent stem cell (iPSC)-based regenerative medicine has substantial potential in the treatment of refractory human diseases. Thus, preclinical studies on the safety and efficacy of these products are essential. Non-human primate (NHP) models such as the rhesus macaque are highly similar to humans in terms of size, lifespan, and immune system, rendering them superior models. However, effective gene transduction in rhesus macaque iPSCs (Rh-iPSCs) remains challenging. In this study, we investigated the effective gene transduction into Rh-iPSCs and its effect on differentiation efficiency. Methods: We established a gene transduction method using the piggyBac transposon vector system. Gene transduced Rh-iPSCs were analyzed for undifferentiated markers. We did teratoma assay to check pluripotency. Gene transduced Rh-iPSCs were differentiated into hematopoietic stem and progenitor cells (HSPCs) and T-cell lineage cells. Additionally, gene transduced Rh-iPSCs were compared the differentiation efficiency with parental Rh-iPSCs. Results: We could establish a gene transduction method using the piggyBac transposon vector system, demonstrating high efficiency and stable transgene expression in Rh-iPSCs. These Rh-iPSCs maintained long-term gene expression while expressing undifferentiated markers. Teratoma assay indicated that these Rh-iPSCs had pluripotency. These Rh-iPSCs could differentiate into HPSCs and T cells that express transgenes. These Rh-iPSCs can differentiate into hematopoietic stem cells and T cells that express transgenes. No significant differences in efficiency of differentiation were observed between parental Rh-iPSCs and these Rh-iPSCs. Conclusions: These results indicate that the piggyBac transposon vector is an excellent gene transfer tool for rhesus macaque iPSCs and could contribute to the advancement of preclinical studies using rhesus macaque iPSCs.

Tolerogenic dendritic cells alleviate collagen-induced arthritis by regulating T-cell differentiation and inhibiting NLRP3-mediated apoptosis.

OBJECTIVE: Tolerogenic dendritic cells (tolDCs) have emerged as a potential treatment for rheumatoid arthritis (RA). However, the detailed mechanism requires further investigation. In this study, we aimed to explore the effects of tolDCs on T-cell differentiation and NLRP3-mediated pyroptosis in a collagen-induced arthritis (CIA) rat model. METHODS: TolDCs were induced using NF-κB ODN decoy. The efficacy of tolDCs intervention in alleviating arthritis symptoms was evaluated in CIA rats. Flow cytometry was employed to analyze CD4+ T-cell subpopulations, while scanning electron microscopy was utilized to observe pyroptosis morphology. Immunohistochemistry was used to assess the expression of pyroptosis-associated proteins. RESULTS: TolDCs intervention significantly reduced joint inflammation and damage in CIA rats. Moreover, it successfully restored the balance of Th1/Th2 cells as well as the balance of Treg/Th17 cells. Furthermore, tolDCs intervention effectively suppressed NLRP3-mediated pyroptosis in the synovium, decreasing the release of IL-1ß and IL-18. CONCLUSION: Our findings underscore the efficacy of tolDCs in attenuating CIA progression through modulation of CD4+ T-cell subpopulations and inhibition of NLRP3-mediated pyroptosis.

Sex-specific differences in ICOS+ T helper cell differentiation in systemic lupus erythematosus patients with low disease activity.

Systemic lupus erythematosus (SLE) is a sex biased chronic autoimmune disease affecting predominantly females during reproductive ages. Changes in the ratio of inducible costimulatory molecule (ICOS)+ regulatory (Treg) and non-regulatory responder (Tresp) CD4+ T cells proved to be crucial for the occurrence of high disease activity. Here, we investigated how the differentiation of ICOS+CD45RA+CD31+ recent thymic emigrant (RTE) Tresps into CD45RA-CD31- memory Tresps affects the percentages of ICOS+ Tresps within total CD4+ T cells. Three different pathways (pathway 1 via CD45RA-CD31+ memory Tresps, pathway 2 via direct proliferation and pathway 3 via resting mature naïve CD45RA+CD31- (MN) cells) were examined in healthy controls and SLE remission patients separated by sex. In female SLE remission patients, immunosuppressive therapy inhibited the ICOS+ RTE differentiation via CD45RA-CD31+ memory Tresps and direct proliferation, leaving an age-independently increased differentiation into CD45RA-CD31- memory Tresps by conversion of resting MN Tresps compared with healthy controls. Due to exhaustion of this pathway with age, no age-dependent change in the percentages of ICOS+ Tresps within total CD4+ T cells could be found. In contrast, no age-independently increased differentiation could be detected in men due to sufficient immunosuppression of all three pathways. This allowed an age-dependent differentiation of ICOS+ RTE Tresps into CD45RA-CD31- memory Tresps by conversion of resting MN Tresps, resulting in age-dependently increasing percentages of ICOS+ Tresps within total CD4+ T cells. We hypothesize that the sex-specific differential effect of immunosuppression on the differentiation of ICOS+ Tresps may explain the sex- and age-dependent occurrence of high disease activity.

Modulation of T Cell Differentiation in Mice with COPD Combined with Lung Cancer Through Key Targets of PD-1 by Tao Hong Si Wu Tang.

The objective is to assess the anti-inflammatory effect of Tao Hong Si Wu Tang combined with anti-PD-1 in a mouse model of COPD combined with lung cancer, elucidating its mechanism through modulation of PD-1/PD-L binding, regulation of Th1/Th2 and Th17/Treg balance, inhibition of IL-4 and IL-17, and promotion of IFN-γ and TGF-ß levels in peripheral blood. One hundred male C57/BL6 mice were randomly allocated to five groups: A (blank control), B (model control), C (THSW), D (anti-PD-1), and E (THSW + anti-PD-1), with 20 mice in each group. The COPD model was induced using fumigation and LPS intra-airway drip, followed by the establishment of lung cancer by Lewis cell inoculation. Treatment groups received Tao Hong Si Wu Tang or/and PD-1 monoclonal antibody. Various indicators were assessed, including macroscopic observation, HE staining of lung tissue, ELISA for cytokines, flow cytometry for cell proportions, and immunohistochemistry/western blotting for protein expression. Lung tissue analysis revealed significant differences between groups, with marked tumor formation observed in groups B-E. Serum levels of IL-4, IFN-γ, IL-17, and TGF-ß were significantly altered, along with changes in CD4 + T/CD8 + T ratio and cytokine-producing cell populations. Expression levels of key proteins were also significantly affected across treatment groups. Tao Hong Si Wu Tang demonstrated anti-inflammatory effects comparable to anti-PD-1, potentially through modulation of PD-1/PD-L binding, correction of Th1/Th2 and Th17/Treg imbalance, and modulation of cytokine levels. These findings suggest a role for Tao Hong Si Wu Tang in ameliorating inflammation and immune dysregulation in COPD combined with lung cancer.

The downregulation of Tapasin in dendritic cell regulates CD8+ T cell autophagy to hamper hepatitis B viral clearance in the induced pluripotent stem cell-derived hepatocyte organoid.

Tapasin, a crucial molecular chaperone involved viral antigen processing and presentation, plays an important role in antivirus immunity. However, its impact on T cell differentiation in the context of virus clearance remains unclear. In this study, we employed induced pluripotent stem cells to differentiate into hepatocyte-like cell, which were subsequently inserted to the inverted colloidal crystal scaffolds, thus establishing a hepatocyte organoid (HO). By inoculating hepatitis B virus (HBV) particles in the system, we successfully engineered a robust in vitro HBV infection model for at least 3 weeks. Furthermore, we aimed to explore the effects of lentivirus-mediated short hairpin RNA (shRNA) targeting human Tapasin on the differentiation and antiviral function of CD8+ T cells. Specifically, we transfected dendritic cells (DCs) with Tapasin-shRNA and cocultured with T cells. The results demonstrated that Tapasin-shRNA transfected DCs effectively suppressed T cell proliferation and impeded HBV-specific cytotoxic T lymphocyte responses. Our investigation also revealed the role of mTOR pathway activation in reducing autophagy activity within CD8+ T cells. Expressions of autophagy-related proteins, beclin-1, LC3II/LC3I were decreased and PI3K/AKT/mTOR activity was increased in Tapasin-shRNA group. Collectively, our findings elucidate that shRNA targeting the Tapasin gene within DCs inhibits T cell differentiation by reducing autophagy activity to hamper viral clearance in the HBV-infected HO.

Impact of vitamin C on the development, differentiation and functional properties of T cells.

Vitamin C plays a multifaceted role in various biological processes and is well-known to facilitate pleiotropic activities in both innate and adaptive immune responses, where the antioxidant capacity of vitamin C is most likely highly relevant since immune responses mainly occur in reducing environments. Beyond its antioxidant properties, vitamin C can enhance the transcription potential of genes by promoting DNA demethylation through ten-eleven-translocation (Tet) methylcytosine dioxygenases, which have been recently demonstrated to be critical for the development and differentiation of T cells. In this minireview, we will provide a broader overview on the impact of vitamin C on signaling and regulatory activities in both innate and adaptive immune cells. Particularly, we will summarize recent findings on the decisive role of finely tuned vitamin C concentrations for T cell development, T helper cell differentiation, and optimal T cell-mediated immune responses.

Decoding the transcriptional heterogeneity, differentiation lineage, clinical significance in tissue-resident memory CD8 T cell of the small intestine by single-cell analysis.

Resident memory T (Trm) cells which are specifically located in non-lymphoid tissues showed distinct phenotypes and functions compared to circulating memory T cells and were vital for the initiation of robust immune response within tissues. However, the heterogeneity in the transcriptional features, development pathways, and cancer response of Trm cells in the small intestine was not demonstrated. Here, we integrated scRNA-seq and scTCR-seq data pan-tissue T cells to explore the heterogeneity of Trm cells and their development pathways. Trm were enriched in tissue-specific immune response and those in the DUO specially interacted with B cells via TNF and MHC-I signatures. T cell lineage analyses demonstrated that Trm might be derived from the T_CD4/CD8 subset within the same organ or migrated from spleen and mesenteric lymph nodes. We compared the immune repertoire of Trm among organs and implied that clonotypes in both DUO and ILE were less expanded and hydrophilic TRB CDR3s were enriched in the DUO. We further demonstrated that Trm in the intestine infiltrated the colorectal cancer and several effector molecules were highly expressed. Finally, the TCGA dataset of colorectal cancer implied that the infiltration of Trm from the DUO and the ILE was beneficial for overall survival and the response to immune checkpoint blockade.

Canine T zone lymphoma is a tumor of mature, previously activated αß T cells.

T cell lymphomas are a diverse group of tumors found in both dogs and humans, originating from various normal T cell types. Identifying the origin of neoplastic lymphocytes can offer valuable insights into the pathogenesis and clinical behavior of these tumors. T zone lymphoma (TZL) in dogs is characterized by the absence of CD45 expression, a strong breed predilection, and its association with adult-onset demodicosis-a condition believed to be linked to immunosuppression. In this study, our aim was to employ transcriptomic and functional data to determine the normal counterpart of TZL. Identifying the normal counterpart may help us understand both how these tumors arise and explain their clinical behavior. Gene expression profiling using NanoString and RNA seq was used to compare the transcriptome between neoplastic T zone cells, normal canine T cells and publicly available gene sets using Gene Set Enrichment Analysis. Mitogen, anti-CD3 stimulation and PMA/ionomycin stimulation were used to assess T cell proliferation in vitro, and intracellular cytokine production was measured by flow cytometry. Gene expression profiling revealed that TZL is most likely derived from an activated or memory alpha-beta T cell but the cells do not fall cleanly into an effector subtype. TZL cells express CD4-specific transcription factors GATA3 and THPOK, even though TZL cells more commonly express CD8, or neither CD4 nor CD8. TZL cells produce high levels of interferon gamma and tumor necrosis factor alpha when stimulated, further supporting the hypothesis that they are derived from an antigen experienced T cell. TZL cells do not proliferate when stimulated through the T cell receptor but will divide when the T cell receptor is bypassed with PMA and ionomycin. The observation that these cells are derived from a mature, previously activated T cell is the first step in understanding the genesis of this unique T cell tumor.

Integrated network pharmacological analysis revealed that Smilax glabra Roxb. alleviates IMQ-induced psoriatic skin inflammation through regulating T cell immune response.

ETHNOPHARMACOLOGICAL RELEVANCE: Psoriasis is an autoimmune disease characterized by dysfunctional T cells and dysregulated immune responses. Smilax glabra Roxb. (SGR) is a formulation used in Traditional Chinese Medicine for the treatment of inflammatory skin disorders, including psoriasis. This study explores the scientific basis for its use by examining the effects of SGR on T cell differentiation and insulin receptor signaling, relevant pathways implicated in the pathophysiology of psoriasis. AIM OF THE STUDY: This study investigates the therapeutic potential of SGR (a Chinese medicine) in psoriasis and its impact on T cell differentiation. MATERIALS AND METHODS: An integrated network pharmacology and bioinformatics approach was employed to elucidate the mechanisms of SGR in regulating T cell differentiation. A psoriasis mouse model was utilized to evaluate the effects of SGR on T cell subsets. Immunohistochemistry and gene expression analyses were conducted to investigate the modulation of insulin receptor signaling pathways by SGR. RESULTS: SGR treatment effectively reset the expression of various T cell subsets in the psoriasis mouse model, suggesting its ability to regulate T cell differentiation and immune function. Furthermore, SGR treatment inhibited insulin receptor signaling and downstream pathways, including PI3K/AKT and ERK, in psoriatic skin lesions. This indicates that SGR may exert its therapeutic effects through modulation of the insulin receptor signaling pathway. CONCLUSIONS: This study provides novel insights into the therapeutic potential of SGR in psoriasis. By modulating T cell differentiation and targeting the insulin receptor signaling pathway, SGR holds promise as a potential treatment option for psoriasis.

Homeodomain-only protein suppresses proliferation and contributes to differentiation- and age-related reduced CD8+ T cell expansion.

T cell activation is a tightly controlled process involving both positive and negative regulators. The precise mechanisms governing the negative regulators in T cell proliferation remain incompletely understood. Here, we report that homeodomain-only protein (HOPX), a homeodomain-containing protein, and its most abundant isoform HOPXb, negatively regulate activation-induced proliferation of human T cells. We found that HOPX expression progressively increased from naïve (TN) to central memory (TCM) to effector memory (TEM) cells, with a notable upregulation following in vitro stimulation. Overexpression of HOPXb leads to a reduction in TN cell proliferation while HOPX knockdown promotes proliferation of TN and TEM cells. Furthermore, we demonstrated that HOPX binds to promoters and exerts repressive effects on the expression of MYC and NR4A1, two positive regulators known to promote T cell proliferation. Importantly, our findings suggest aging is associated with increased HOPX expression, and that knockdown of HOPX enhances the proliferation of CD8+ T cells in older adults. Our findings provide compelling evidence that HOPX serves as a negative regulator of T cell activation and plays a pivotal role in T cell differentiation and in age-related-reduction in T cell proliferation.

Reversible, tunable epigenetic silencing of TCF1 generates flexibility in the T cell memory decision.

The immune system encodes information about the severity of a pathogenic threat in the quantity and type of memory cells it forms. This encoding emerges from lymphocyte decisions to maintain or lose self-renewal and memory potential during a challenge. By tracking CD8+ T cells at the single-cell and clonal lineage level using time-resolved transcriptomics, quantitative live imaging, and an acute infection model, we find that T cells will maintain or lose memory potential early after antigen recognition. However, following pathogen clearance, T cells may regain memory potential if initially lost. Mechanistically, this flexibility is implemented by a stochastic cis-epigenetic switch that tunably and reversibly silences the memory regulator, TCF1, in response to stimulation. Mathematical modeling shows how this flexibility allows memory T cell numbers to scale robustly with pathogen virulence and immune response magnitudes. We propose that flexibility and stochasticity in cellular decisions ensure optimal immune responses against diverse threats.

BATF-mediated regulation of exhausted CD8+ T-cell responses and potential implications for chimeric antigen receptor-T therapy.

Chimeric antigen receptor (CAR) T-cell therapy for malignant tumors has reached a crucial stage, with recent studies underscoring the role of T-cell exhaustion in determining the efficacy of CAR-T therapy. This trailblazing discovery has opened new avenues to augment the potency of CAR-T therapy. Basic leucine zipper ATF-like transcription factor (BATF) is indispensable in alleviating T-cell exhaustion and is pivotal in the early stages of CD8+ T-cell differentiation. In cooperation with other transcription factors, it plays a key role in the differentiation and maturation processes of exhausted T cells. A deeper comprehension of BATF's mechanisms in T-cell biology may yield novel insights into amplifying the efficacy of CAR-T therapy.

Chimeric antigen receptor (CAR) T-cell therapy, a treatment that boosts the body's immune system to fight cancer, has made significant progress. Recent research has shown that T-cell exhaustion, which is when the body's immune cells become less effective, affects how well this therapy works. This finding has opened new possibilities to make CAR-T therapy more effective. There is a specific protein called BATF that plays an important role in reducing T-cell exhaustion and influencing the early development of certain immune cells. This review describes how BATF interacts with exhausted T cells, to improve CAR-T therapy. By understanding how BATF works in the immune system, new ways to enhance CAR-T therapy and its ability to fight cancer may be found.