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Age-associated B cells (ABCs) are a transcriptionally and functionally unique B cell population. In addition to arising with age and following infection, ABCs are expanded during autoimmune disease, including those with systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis. The exact nature of how ABCs impact disease remains unclear. Here, we review what is known regarding ABC development and distribution during diseases including systemic lupus erythematosus, multiple sclerosis, and rheumatoid arthritis. We discuss possible mechanisms by which ABCs could contribute to disease, including the production of cytokines and autoantibodies or stimulation of T cells. Finally, we speculate on how ABCs might act as mediators between sex, infection, and autoimmune disease, and discuss avenues for further research.

T-cell exhaustion is a phenomenon of dysfunction or physical elimination of antigen-specific T cells reported in human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) infections as well as cancer. Exhaustion appears to be often restricted to CD8+ T cells responses in the literature, although CD4+ T cells have also been reported to be functionally exhausted in certain chronic infections. Although our understanding of the molecular mechanisms associated with the transcriptional regulation of T-cell exhaustion is advancing, it is imperative to also explore the central mechanisms that control the altered expression patterns. Targeting metabolic dysfunctions with mitochondrion-targeted antioxidants are also expected to improve the antiviral functions of exhausted virus-specific CD8+ T cells. In addition, it is crucial to consider the contributions of mitochondrial biogenesis on T-cell exhaustion and how mitochondrial metabolism of T cells could be targeted whilst treating chronic viral infections. Here, we review the current understanding of cardinal features of T-cell exhaustion in chronic infections, and have attempted to focus on recent discoveries, potential strategies to reverse exhaustion and reinvigorate optimal protective immune responses in the host.

Thalidomide and its analogues are known as immunomodulatory drugs (IMiDs) that possess direct antimyeloma effects, in addition to other secondary effects, including antiangiogenic, antiinflammatory, and immunomodulatory effects. Although the involvement of natural killer (NK) cells in the antitumor effects of IMiDs has been reported, it is unclear whether IMiDs inhibit cancer cell metastasis by regulating the antitumor function of NK cells. In this study, we examined the protective effects of thalidomide against cancer metastasis by focusing on its immunomodulatory effects through NK cells. Using experimental lung metastasis models, we found that pharmacological effects of thalidomide on host cells, but not its direct anticancer tumor effects, are responsible for the inhibition of lung metastases. To exert the antimetastatic effects of thalidomide, both γ‐interferon (IFN‐γ) production and direct cytotoxicity of NK cells were essential, without notable contribution from T cells. In thalidomide‐treated mice, there was a significant increase in the terminally differentiated mature CD27lo NK cells in the peripheral tissues and NK cells in thalidomide‐treated mice showed significantly higher cytotoxicity and IFN‐γ production. The NK cell expression of T‐bet was upregulated by thalidomide treatment and the downregulation of glycogen synthase kinase‐3β expression was observed in thalidomide‐treated NK cells. Collectively, our study suggests that thalidomide induces the functional maturation of peripheral NK cells through alteration of T‐bet expression to inhibit lung metastasis of cancer cells. In this study, we examined the antimetastatic effects of thalidomide by focusing on its immunomodulatory effects through natural killer (NK) cells. Our study suggests that thalidomide induces the functional maturation of peripheral NK cells likely through alteration of T‐bet expression, to inhibit lung metastasis of cancer cells.

T‐bet, encoded by TBX21, is extensively expressed across various immune cell types, and orchestrates critical functions in their development, survival, and physiological activities. However, the role of T‐bet in non‐immune compartments, notably the epithelial cells, remains obscure. Herein, a Tet‐O‐T‐bet transgenic mouse strain is generated for doxycycline‐inducible T‐bet expression in adult animals. Unexpectedly, ubiquitous T‐bet overexpression causes acute diarrhea, intestinal damage, and rapid mortality. Cell‐type‐specific analyses reveal that T‐bet‐driven pathology is not attributable to its overexpression in CD4+ T cells or myeloid lineages. Instead, inducible T‐bet overexpression in the intestinal epithelial cells is the critical determinant of the observed lethal phenotype. Mechanistically, T‐bet overexpression modulates ion channel and transporter profiles in gut epithelial cells, triggering profound fluid secretion and subsequent lethal dehydration. Furthermore, ectopic T‐bet expression enhances gut epithelial cell apoptosis and markedly suppresses colon cancer development in xenograft models. Collectively, the findings unveil a previously unrecognized role of T‐bet in intestinal epithelial cells for inducing apoptosis, diarrhea, and local inflammation, thus implicating its potential as a therapeutic target for the treatment of cancer and inflammatory diseases. This work presents a novel role of T‐bet in the intestinal epithelial cells. In healthy transgenic mice, induction of T‐bet expression promotes cell apoptosis and regulates ion channel and transporter profiling, leading to diarrhea, tissue damage, and mortality. However, in tumor‐bearing mice, ectopic T‐bet expression effectively inhibits colon cancer development, indicating a promising therapeutic potential in cancer treatment.

Historically, multiple sclerosis (MS) has been viewed as being primarily driven by T cells. However, the effective use of anti-CD20 treatment now also reveals an important role for B cells in MS patients. The results from this treatment put forward T-cell activation rather than antibody production by B cells as a driving force behind MS. The main question of how their interaction provokes both B and T cells to infiltrate the CNS and cause local pathology remains to be answered. In this review, we highlight key pathogenic events involving B and T cells that most likely contribute to the pathogenesis of MS. These include (1) peripheral escape of B cells from T cell-mediated control, (2) interaction of pathogenic B and T cells in secondary lymph nodes, and (3) reactivation of B and T cells accumulating in the CNS. We will focus on the functional programs of CNS-infiltrating lymphocyte subsets in MS patients and discuss how these are defined by mechanisms such as antigen presentation, co-stimulation and cytokine production in the periphery. Furthermore, the potential impact of genetic variants and viral triggers on candidate subsets will be debated in the context of MS.

Regulatory T cells expressing the transcription factor T-bet selectively suppress T H 1 and CD8 T cells, but not T H 2 or T H 17 activation and associated autoimmunity. Adaptive immune responses are tailored to different types of pathogens through differentiation of naive CD4 T cells into functionally distinct subsets of effector T cells (T helper 1 (T H 1), T H 2, and T H 17) defined by expression of the key transcription factors T-bet, GATA3, and RORγt, respectively 1 . Regulatory T (T reg ) cells comprise a distinct anti-inflammatory lineage specified by the X-linked transcription factor Foxp3 (refs 2 , 3 ). Paradoxically, some activated T reg cells express the aforementioned effector CD4 T cell transcription factors, which have been suggested to provide T reg cells with enhanced suppressive capacity 4 , 5 , 6 . Whether expression of these factors in T reg cells—as in effector T cells—is indicative of heterogeneity of functionally discrete and stable differentiation states, or conversely may be readily reversible, is unknown. Here we demonstrate that expression of the T H 1-associated transcription factor T-bet in mouse T reg cells, induced at steady state and following infection, gradually becomes highly stable even under non-permissive conditions. Loss of function or elimination of T-bet-expressing T reg cells—but not of T-bet expression in T reg cells—resulted in severe T H 1 autoimmunity. Conversely, following depletion of T-bet − T reg cells, the remaining T-bet + cells specifically inhibited T H 1 and CD8 T cell activation consistent with their co-localization with T-bet + effector T cells. These results suggest that T-bet + T reg cells have an essential immunosuppressive function and indicate that T reg cell functional heterogeneity is a critical feature of immunological tolerance.

Whole blood transcriptional signatures distinguishing active tuberculosis patients from asymptomatic latently infected individuals exist. Consensus has not been achieved regarding the optimal reduced gene sets as diagnostic biomarkers that also achieve discrimination from other diseases. Here we show a blood transcriptional signature of active tuberculosis using RNA-Seq, confirming microarray results, that discriminates active tuberculosis from latently infected and healthy individuals, validating this signature in an independent cohort. Using an advanced modular approach, we utilise the information from the entire transcriptome, which includes overabundance of type I interferon-inducible genes and underabundance of IFNG and TBX21 , to develop a signature that discriminates active tuberculosis patients from latently infected individuals or those with acute viral and bacterial infections. We suggest that methods targeting gene selection across multiple discriminant modules can improve the development of diagnostic biomarkers with improved performance. Finally, utilising the modular approach, we demonstrate dynamic heterogeneity in a longitudinal study of recent tuberculosis contacts. Mass screening diagnostics for Mycobacterium tuberculosis exist, but criticisms exist regarding the sensitivity and specificity of these tools. Here the authors use RNA-Seq and a modular bioinformatics approach using data from their own cohorts and meta-analysis of published cohorts to create a reduced signature for detection of tuberculosis that does not detect other diseases.

Distinct from conventional Foxp3 + regulatory T cells (Tregs), T-bet + Tregs represent a stable subset of immunosuppressive T cells characterized by co-expression of the transcription factors (TFs) Foxp3 and T-bet. Given that Tregs were also reported to co-express Foxp3 together with effector T cell TFs such as GATA3, or RORγt, we propose the term hybrid Tregs (hTregs) to distinguish between these Tregs that co-express Foxp3 together with effector T cell TFs from conventional Foxp3 + Tregs. Therefore, this review will focus on hTreg cells, a specific subset of CD4 + T cells, and discuss the different types of hTregs with particular emphasis on T-bet + hTregs. T-bet + hTregs exhibit unique features including IFN-γ production, high expression of immune checkpoints (PD-1, CTLA-4, GITR, OX40, TIGIT), and chemokine receptors (CXCR3, CCR5). Through secretion of IL-10, TGF-β and IFN-γ, T-bet + hTregs modulate both innate and adaptive immune responses within the tumor microenvironment (TME). Their high expression of CD73 contributes to adenosine-mediated immunosuppression, while CXCR3 and CCR5 facilitate their recruitment to inflammatory sites. T-bet + hTregs were reported to accumulate in multiple human cancers, including lung, ovarian, and colorectal carcinomas. Despite these advancements, the function of hTregs in diseases such as cancer remains poorly understood, and requires further investigations. For instance, some studies suggest T-bet+ hTregs to be anti-inflammatory due to their production of IL-10, TGF-β, and superior suppressive capacity compared to conventional Tregs. Yet, other studies have reported that T-bet + hTregs exhibit enhanced proinflammatory functions in colitis and other pathologies. We will then highlight current known mechanisms that promote the differentiation and functions of T-bet + hTregs in cancer. Lastly, we will discuss the advancements and opportunities for therapeutic targeting of T-bet+ hTregs in cancer immunotherapy.

Eomesodermin (Eomes) is a critical factor in the development of natural killer (NK) cells, but its precise role in temporal and spatial coordination during this process remains unclear. Our study revealed that Eomes plays distinct roles during the early and late stages of NK cell development. Specifically, the early deletion of Eomes via the CD122-Cre transgene resulted in significant blockade at the progenitor stage due to the downregulation of KLF2, another important transcription factor. ChIP-seq revealed direct binding of Eomes to the conserved noncoding sequence (CNS) of Klf2 . Utilizing the CHimeric IMmune Editing (CHIME) technique, we found that deletion of the CNS region of Klf2 via CRISPRi led to a reduction in the NK cell population and developmental arrest. Moreover, constitutive activation of this specific CNS region through CRISPRa significantly reversed the severe defects in NK cell development caused by Eomes deficiency. Conversely, Ncr1-Cre- mediated terminal deletion of Eomes expedited the transition of NK cell subsets from the CD27 + CD11b + phenotype to the CD27 − CD11b + phenotype. Late-stage deficiency of Eomes led to a significant increase in T-bet expression, which subsequently increased the expression of the transcription factor Zeb2. Genetic deletion of one allele of Tbx21 , encoding T-bet, effectively reversed the aberrant differentiation of Eomes-deficient NK cells. In summary, we utilized two innovative genetic models to elucidate the intricate mechanisms underlying Eomes-mediated NK cell commitment and differentiation.

T-bet is a transcription factor predominantly expressed in immune cells, and it has been associated with a range of physiological and pathological processes, including the differentiation of various immune cell types, the development of immune-related diseases, and tumor progression. Despite notable advancements in the field, current research on T-bet remains fragmented, primarily concentrating on functional studies within specific cell types or the progression of particular diseases. This review aims to provide a comprehensive synthesis of the most recent findings regarding the role of T-bet in various diseases, with an emphasis on elucidating its molecular mechanisms and potential clinical applications. We underscore the involvement of T-bet in the pathogenesis of systemic diseases, including autoimmune disorders, infectious diseases, allergic conditions, endocrine disorders, psychiatric illnesses, and chromosomal abnormalities. Furthermore, we summarize its role in the development of various malignant tumors, such as esophageal cancer, gastric cancer, breast cancer, colon cancer, prostate cancer, and hematological malignancies. Additionally, we discuss the impact of T-bet on several critical processes in tumor biology, including tumor cell proliferation, apoptosis, epithelial-mesenchymal transition (EMT), metastasis, immune cell infiltration, and iron-induced apoptosis. We also assess the potential of T-bet as a prognostic and therapeutic target for tumors. In conclusion, T-bet may serve as a significant biomarker for the diagnosis and treatment of immune disorders and cancer, as well as a target for innovative immunotherapeutic strategies aimed at addressing tumors and immune-related diseases.