{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nT‐bet, a T‐box transcription factor, is central to orchestrating adaptive immune responses by promoting type 1 cell fates. In CD4⁺ T cells, T‐bet drives Th1 lineage commitment by inducing interferon‑γ (IFN‑γ) and repressing opposing Th2 programs, thereby restricting allergic inflammation and asthma‐like pathology. Its expression, initiated by IFN‑γ/STAT1 signals, is critical not only for optimal Th1 differentiation but also for modulating proinflammatory responses in T cell–mediated colitis and autoimmune settings. Moreover, T‐bet regulates CD8⁺ T cell differentiation, influencing the balance between short‐lived effector cells and central–memory precursors, and plays a key role in shaping cytokine profiles and cytotoxic functions. These integrated activities rely on T‐bet’s interactions with other lineage‐defining factors and signal transduction pathways that couple metabolic checkpoints (e.g. mTOR activation) to transcriptional programming."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond conventional T cells, T‐bet also modulates the functions of nonclassical lymphocytes and antigen‐presenting cells that are vital for innate as well as orchestrated adaptive immunity. In dendritic cells, T‐bet supports optimal IFN‑γ production, thereby reinforcing Th1 polarization. In the natural killer (NK) cell compartment, T‐bet governs cellular maturation, migratory egress, and responsiveness to sphingosine‑1‑phosphate gradients—with its activity counterbalanced by negative regulators such as Foxo1. In innate lymphoid cells (ILCs), particularly those expressing NKp46, T‐bet is indispensable for their differentiation and effector functions that contribute to mucosal barrier integrity and host defense. Through these mechanisms, T‐bet not only promotes type 1 immunity but also ensures proper intercellular crosstalk during inflammatory and autoimmune processes."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nT‐bet further influences humoral immunity by directing class‐switch recombination in B cells and shaping memory B cell subset identity. Its activity facilitates IFN‑γ–mediated IgG2a/c production, thereby enhancing antiviral antibody responses and, in some contexts, contributing to the development of autoantibodies in systemic autoimmunity. Through these B cell–intrinsic programs, T‐bet ensures the durability of neutralizing titers, as evidenced by its role in establishing long‐lived and functionally distinct memory B cell pools."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "36", "end_ref": "39"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCollectively, T‐bet’s multilayered functions—from driving transcriptional programs for IFN‑γ production and cytotoxicity in T cells to regulating differentiation, migration, and effector responses in innate lymphocytes and B cells—establish it as a master regulator of type 1 immunity. Its tight regulation ensures effective host defense while limiting immunopathology, a balance underscored by its roles in diverse disease models such as experimental autoimmune encephalomyelitis, inflammatory bowel disease, atherosclerosis, and viral infections. These insights have further spurred translational strategies, including engineered immunotherapies that harness T‐bet–high effector phenotypes for enhanced anti‑tumor responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}, {"type": "fg_fs", "start_ref": "21", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Susetta Finotto, Markus F Neurath, Jonathan N Glickman, et al. 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