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Various inhibitors targeting T-cell immunoglobulin and mucin-containing molecule 3 (TIM3) aimed at reversing T-cell exhaustion for better immunotherapy outcomes have demonstrated limited clinical efficacy as monotherapy, with the underlying mechanisms remaining ambiguous. TIM3 is markedly expressed in dendritic cells (DCs), and the inconsistent research findings on its role in myeloid cells underscore its vital function within DCs. Through the establishment of an in vitro differentiation model generating mature dendritic cells (mDCs) under TIM3-targeted interventions, combined with an RNA sequencing analysis, this investigation systematically examined TIM3-mediated regulation and ligand interactions in human primary DCs. The findings indicate that TIM3 inhibition hinders DC maturation, which subsequently diminishes the antigen-presenting capacity of DCs, ultimately leading to immune suppression in T cells. These findings collectively establish TIM3 as a regulator of DC differentiation that promotes DC maturation while optimizing the antigen-processing and presentation capacity. This study elucidates the rationale behind the suboptimal efficacy of TIM3 inhibitors and advocates for retaining TIM3 signaling pathways in DCs.

Menopause not only affects fertility but also has widespread impact on systemic health. Yet, the molecular mechanisms underlying this process are not fully understood, partly due to the absence of robust, age-relevant preclinical models with comprehensive molecular and phenotypic characterization. To address this, we systematically compared three candidate mouse models of menopause: (1) intact aging, (2) chemical ovarian follicle depletion using 4-vinylcyclohexene diepoxide (VCD) administered at multiple ages, and (3) Foxl2 haploinsufficiency, a genetic model based on a transcription factor linked to human premature ovarian failure. Through histology, serum hormone profiling, single-cell transcriptomics and machine-learning approaches, we uncovered both shared and model-specific features of follicle loss, endocrine disruption, and transcriptional remodeling. The VCD and Foxl2 haploinsufficiency models revealed distinct patterns of hormonal and immune alterations not captured by intact aging alone. This comparative framework enables informed selection of context-appropriate preclinical rodent models to study menopause and the broader physiological consequences of ovarian aging.

Neutrophils are highly abundant in the oral mucosal tissues, and their balanced activation and clearance are essential for immune homeostasis. Here, we demonstrate that neutrophils infected with the bacterial pathogen Porphyromonas gingivalis (Pg) are captured alive by macrophages in a manner that bypasses all known receptor-ligand interactions involved in the phagocytosis of either live or dead cells. Mechanistically, upon interaction with Pg, or its protease RgpB (gingipains), live neutrophils undergo rapid remodeling of their proteomes, generating neoepitopes. N-terminomics-based proteomic profiling identified multiple RgpB cleavage sites on several azurophilic granule proteins that are translocated to the surface of live neutrophils via low-level degranulation and activate macrophage ¦ÁM¦Â2 integrin receptors, thus mediating internalization of non-apoptotic neutrophils within macrophage phagosomes. Macrophages with entrapped live neutrophils exhibit phenotypic and transcriptional reprogramming, consistent with inflammatory outcomes in vitro and in vivo. In contrast to the immunosuppressive outcomes associated with efferocytosis of apoptotic neutrophils, live neutrophil entrapment failed to fully activate several catabolic and metabolic processes and exhibited a defective activation of PPAR-¦Ã mediated pro-resolution pathways, thereby promoting bacterial persistence and hindering the resolution of inflammation. Thus, our data demonstrate a novel immune subversion strategy unique to Pg and reveal a previously unknown mode of live neutrophil sequestration into macrophages during an infection.