The Role of the KLF Family in T-Cell-Mediated Regulation of Cardiovascular Diseases: Molecular Mechanisms and Therapeutic Prospects

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  Figure 1. Functional spectrum and evidence hierarchy of prioritized KLF family members in T-cell biology. KLF2 regulates quiescence-associated transcription and SELL/CD62L- and S1PR1-dependent trafficking and recirculation. KLF10 supports TGF-β-responsive transcription, Treg suppressive competence, and metabolic and migratory fitness, with TGFBR2 regulation demonstrated in a subset-dependent context. KLF4 directly promotes Il17a transcription and contributes to Th17-associated inflammatory differentiation. KLF13 regulates delayed CCL5/RANTES expression and represses the anti-apoptotic protein BCL-XL, thereby exerting a survival-restraining effect; the latter evidence is derived predominantly from thymocyte models. Evidence within general T-cell biology ranges from established molecular or functional evidence to context-dependent observations, whereas cardiovascular evidence is strongest for KLF10 manipulation within the CD4+ T-cell lineage in experimental atherosclerosis; Treg-focused functional studies support involvement of regulatory T-cell mechanisms without establishing exclusively Treg-intrinsic causality. Filled, half-filled, and open circles denote direct disease-specific evidence,…

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  Figure 2. Disease-specific T-cell landscapes and KLF evidence across major cardiovascular diseases. T-cell functions vary according to subset identity, anatomical localization, disease stage, and interactions with cardiovascular, myeloid, and stromal cells. Across atherosclerosis, myocardial infarction, myocarditis, hypertension, and heart failure, effector T-cell responses contribute to inflammation and tissue injury, whereas regulatory T-cell programs may restrain inflammation or support repair in a context- and stage-dependent manner. The strength of evidence for KLF-dependent T-cell mechanisms differs substantially among diseases: direct disease-specific evidence is strongest for KLF10 manipulation within the CD4+ T-cell lineage in experimental atherosclerosis, with complementary functional evidence implicating Treg–macrophage interactions without establishing exclusively Treg-intrinsic causality; KLF2 in atherosclerosis and KLF2/KLF10 in myocardial infarction are supported by emerging mechanistic evidence; and proposed KLF-dependent mechanisms in myocarditis, hypertension, and heart failure remain hypothesis-generating. Filled, half-filled, and open circles denote direct…

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  Figure 3. Core molecular signaling logic of the KLF–T-cell axis. Antigen and co-stimulatory signals, TGF-β, inflammatory cytokines, and tissue-metabolic stress converge on signaling pathways that shape distinct KLF-dependent T-cell programs. PI3K–Akt–mTOR signaling restrains FOXO1 and thereby influences the KLF2-dependent SELL/CD62L and S1PR1 trafficking program. TGF-β–SMAD2/3–SMAD4 signaling intersects with KLF10-dependent regulation of TGFBR2-mediated responsiveness in CD8+ T cells and with Treg suppressive competence and metabolic fitness in a subset-dependent manner. The canonical STAT3–RORγt pathway and KLF4-dependent Il17a transcription converge on Th17/IL-17 differentiation, while HIF-1α-associated metabolic signaling provides an additional context-dependent input into the Th17 program. KLF13 regulates delayed CCL5/RANTES expression and represses the anti-apoptotic protein BCL-XL, thereby promoting apoptosis-associated survival restraint; the latter evidence is derived predominantly from thymocyte models. At the cardiovascular disease level, direct disease-specific evidence is strongest for KLF10 manipulation within the CD4+ T-cell lineage in experimental atherosclerosis; evidence…

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  Figure 4. Translational framework for therapeutic strategies related to the KLF–T-cell axis. Therapeutic strategies are organized into complementary evidence and translational domains rather than a linear sequence of maturity. Low-dose IL-2 provides adjacent clinical evidence that preferential Treg expansion is therapeutically tractable in selected immune-mediated settings but does not directly target a KLF. Adoptive and engineered Treg approaches provide predominantly preclinical evidence that regulatory T-cell states can be therapeutically manipulated, including in cardiovascular injury models. KLF-oriented strategies remain therapeutically unvalidated: the strongest direct disease-specific evidence derives from KLF10 manipulation within the CD4+ T-cell lineage in experimental atherosclerosis, whereas KLF2 is supported primarily by emerging mechanistic evidence and KLF4- and KLF13-oriented concepts remain hypothesis-generating. T-cell-targeted nanoparticles, nucleic-acid delivery, CRISPR-based regulation, and ex vivo cell engineering represent enabling technologies rather than validated KLF-directed therapies. Cross-cutting translational barriers include cell- and subset-specific…