Biology subjects

Narasimhan, H.

Publications and source records attributed to Narasimhan, H..

9 recordsLinked to original sources

bioRxiv2026

A transient CD87-centred axis enhances the Th17 potential of cDC2 in neonates

Type 2 conventional dendritic cells (cDC2) orchestrate T cell immunity, yet the signals that regulate their tissue-specific functions across development remain poorly defined. We demonstrate that splenic cDC2/DC3 subset heterogeneity is established perinatally and that splenic ESAMhi cDC2A undergo a transcriptional and functional transition around the time of weaning, which occurs independently of microbiota. Comparative transcriptomics identified neonatal-specific regulatory programs, including elevated expression of Plaur, encoding CD87/uPAR. CD87 sensitizes neonatal ESAMhi cDC2A to coagulation factor XII (FXII), thereby enhancing their capacity to promote Th17 differentiation. In human infants, CD87 expression was high on cDC2, its expression declined with age and in plasma of preterm infants CD87 positively correlated with Th17-associated cytokines. Together, we identify a conserved link between coagulation pathways and cDC2 developmental programming that may offer new opportunities to modulate Th17 responses in infancy. SummarySplenic cDC2 undergo a transcriptional and functional remodeling around weaning. Elevated CD87 expression on neonatal cDC2 enhances their FXII-driven Th17 potential. Conserved in human infants, elevated CD87 expression reveals a coagulation-linked pathway shaping early-life dendritic cell function and suggests targets to improve vaccination.

immunology↗

bioRxiv2026

Periweaning diet-induced activation of an IFNγ-mediated regulatory circuit promotes the homeostasis of cytotoxic CD8+ T Cells

Balancing pathogen defence with maintaining tolerance to environmental antigens, such as food or commensals, in neonates is essential for survival and the establishment of life-long immune homeostasis. Instructed by environmental signals type 1 conventional dendritic cells (cDC1) drive either T cell tolerance or immunity. Here, we uncover an interferon (IFN)-{gamma}-driven regulatory circuit in early life that relays dietary cues to spleen cDC1. Loss-of-function demonstrates that IFN{gamma}-mediated STAT1-signaling induces an immunogenic maturation program in spleen cDC1 that instructs cDC1 to expand effector memory CD8 T cells. This program emerges during weaning, when IFN{gamma} production from lymphocytes rises, it occurs in germ-free mice and remains responsive to dietary intervention in adult mice. During the transition from breastfeeding to solid food at weaning, this circuit relays dietary information to spleen cDC1 to shape the effector phenotype of food-antigen specific CD8+ T cells in a feed-forward manner, allowing cDC1 to recalibrate the T cell pool at the moment of nutritional independence.

immunology↗

bioRxiv2026

An immune-poised state of human bronchial epithelial cells mediates RSV resistance in adults

Respiratory syncytial virus (RSV) impairs STAT3 activation in infected ciliated cells in infants, but not adults, causing apoptosis to facilitate virus spread. How age regulates the STAT3 response to RSV in human bronchial epithelial cells (BEpiCs) is unknown. Here, we identify an age-associated immune-poised physiological state in human bronchial basal stem cells (BSCs) and progeny BEpiCs, rendering robust RIG-I to guard against the inactivation of RIG-I-STAT3 signaling by RSV nonstructural protein 2. In contrast, infant BEpiCs are vulnerable to such inactivation by RSV due to lower RIG-I levels. We show that acute respiratory viral infection in specific pathogen-free mice, rather than physical age, triggered sustained epigenetic and transcriptomic remodeling in BEpiCs that resembled age-associated changes in human BEpiCs. In addition, cytokine pretreatment of human neonatal BSCs induced an adult-like immune-poised state that was maintained in progeny BEpiCs to protect against RSV. Therefore, respiratory infection and inflammation during a lifetime imparts the effect of age to BSCs, which fortifies RIG-I in progeny cells to mediate RSV resistance.

microbiology↗

bioRxiv2025

Temporal single-cell profiling uncovers age-associated delays in immune resolution to respiratory viral infection

Aging is a major risk factor for increased morbidity and mortality following acute respiratory virus infections. To elucidate the immune determinants underlying viral pathogenesis and delayed lung repair in the aged lung, a comprehensive time-course study was conducted. Single-cell RNA sequencing (scRNAseq) and high-dimensional flow cytometry were utilized to compare lungs from young and aged mice infected with influenza A virus (IAV). Aged hosts displayed diminished alveolar macrophage (AM) and dendritic cell (DC) but elevated monocyte-derived macrophage (MoM) and interstitial macrophage (IM) presence following infection. Additionally, enhanced accumulation of adaptive immune cells, including CD4+ tissue-resident helper (TRH) cells, CD8+ tissue-resident memory (TRM) cells, and a B cell subset resembling age-associated B cells, was observed in the memory phase. Pathway analysis revealed that elevated type I and II interferon (IFN/{gamma}) signaling, especially in MoM/IM subsets, distinguished the aged hosts from the young. Inhibition of IFN/{gamma} signaling after viral clearance improved long-term respiratory outcomes and reduced both IM and TRH populations in aged mice. These findings highlight the pivotal role of IFN/{gamma} signaling, likely within MoM/IM subsets, in driving the exuberant persistence of adaptive immune cells and chronic immunopathology in the aged lung following acute viral infection.

immunology↗

bioRxiv2024

Cross-species analyses reveal RORγt-expressing dendritic cells are a lineage of antigen presenting cells conserved across tissues

Conventional dendritic cells (cDCs) are potent antigen presenting cells (APCs) that exhibit tissue and age-specific diversity allowing them to direct situation-adapted immunity. Thereby they harbor great potential for being targeted in vaccination and cancer. Here, we resolve conflicting data about expression of retinoic acid receptor-related orphan receptor-{gamma}t (ROR{psi}t) in cDCs. We show that ROR{psi}t+ DCs exist in murine lymphoid and non-lymphoid tissues across age. Fate mapping, functional assays and single cell multiomic profiling reveal these cells as ontogenetically and transcriptionally distinct from other well characterized cDC subtypes, as well as from ROR{psi}t+ type 3 innate lymphocytes (ILC3s). We show that ROR{psi}t+ DCs can migrate to lymph nodes and activate naive CD4+ T cells in response to inflammatory triggers. Comparative and cross-species transcriptomics revealed homologous populations in human spleen, lymph nodes and intestines. Further, integrated meta-analyses aligned ROR{psi}t+ DCs identified here with other emerging populations of ROR{psi}t+APCs, including R-DC-like cells, Janus cells/extrathymic Aire expressing cells (eTACs) and subtypes of Thetis cells. While ROR{psi}t+APCs have primarily been linked to T cell tolerance, our work establishes ROR{psi}t+ DCs as unique lineage of immune sentinel cells conserved across tissues and species that expands the functional repertoire of ROR{psi}t+ APCs beyond promoting tolerance. One sentence summaryROR{gamma}t+ DC exhibit versatile APC functions and are a distinct immune lineage conserved across age, tissues and species that entails Thetis cells, Janus cells/ROR{gamma}t+ eTACs and R-DC-like cells.

immunology↗

bioRxiv2023

Proximal immune-epithelial progenitor interactions drive chronic tissue sequelae post COVID-19

The long-term physiological consequences of SARS-CoV-2, termed Post-Acute Sequelae of COVID-19 (PASC), are rapidly evolving into a major public health concern. The underlying cellular and molecular etiology remain poorly defined but growing evidence links PASC to abnormal immune responses and/or poor organ recovery post-infection. Yet, the precise mechanisms driving non-resolving inflammation and impaired tissue repair in the context of PASC remain unclear. With insights from three independent clinical cohorts of PASC patients with abnormal lung function and/or viral infection-mediated pulmonary fibrosis, we established a clinically relevant mouse model of post-viral lung sequelae to investigate the pathophysiology of respiratory PASC. By employing a combination of spatial transcriptomics and imaging, we identified dysregulated proximal interactions between immune cells and epithelial progenitors unique to the fibroproliferation in respiratory PASC but not acute COVID-19 or idiopathic pulmonary fibrosis (IPF). Specifically, we found a central role for lung-resident CD8+ T cell-macrophage interactions in maintaining Krt8hi transitional and ectopic Krt5+ basal cell progenitors, thus impairing alveolar regeneration and driving fibrotic sequelae after acute viral pneumonia. Mechanistically, CD8+ T cell derived IFN-{gamma} and TNF stimulated lung macrophages to chronically release IL-1{beta}, resulting in the abnormal accumulation of dysplastic epithelial progenitors and fibrosis. Notably, therapeutic neutralization of IFN-{gamma} and TNF, or IL-1{beta} after the resolution of acute infection resulted in markedly improved alveolar regeneration and restoration of pulmonary function. Together, our findings implicate a dysregulated immune-epithelial progenitor niche in driving respiratory PASC. Moreover, in contrast to other approaches requiring early intervention, we highlight therapeutic strategies to rescue fibrotic disease in the aftermath of respiratory viral infections, addressing the current unmet need in the clinical management of PASC and post-viral disease.

immunology↗

bioRxiv2022

Loss of Bcl6 transcriptionally alters classical dendritic cells and diminishes T follicular helper cell-inducing cDC2 in mouse spleen

Conventional dendritic cells (cDC) play key roles in immune induction, but what drives their heterogeneity and functional specialization is still ill-defined. Here we show that cDC-specific deletion of the transcriptional repressor Bcl6 in mice alters the phenotype and transcriptome of cDC1s and cDC2s, while their lineage identity is preserved. Bcl6-deficient cDC1s are diminished in the periphery but maintain their ability to cross-present antigen to CD8+ T cells, confirming general maintenance of this subset. Surprisingly, the absence of Bcl6 in cDCs causes a complete loss of Notch2-dependent cDC2s in the spleen and intestinal lamina propria. DC-targeted Bcl6-deficient mice induced fewer T follicular helper cells despite a profound impact on T follicular regulatory cells in response to immunization and mounted diminished Th17 immunity to Citrobacter rodentium in the colon. Our findings establish Bcl6 as an essential transcription factor for subsets of cDC and add to our understanding of the transcriptional landscape underlying cDC heterogeneity.

immunology↗

bioRxiv2022

Single cell RNA sequencing reveals mechanisms underlying a senescence-like phenotype of Alveolar Macrophages during Aging

Alveolar Macrophages (AMs) are unique innate immune cells that reside in the alveolar space and accommodate the ever-changing needs of the lungs against internal and external challenges. During homeostasis, AMs maintain themselves through self-renewal without input from adult hematopoietic stem cells. Currently, little is known regarding the influence of aging on AM dynamics, heterogeneity and transcriptional profiles. Here, we identified CBF{beta} as an indispensable transcription factor that ensures AM self-renewal. Deficiency in CBF{beta} led to decreased proliferation and self-renewal ability of AMs. Moreover, with single cell RNA sequencing analysis of AMs from young and aged mice, we discovered that despite similarities in the transcriptome of proliferating cells, AMs from the aged mice exhibited reduced embryotic stem cell-like features. Aged AMs also showed diminished capacity for DNA repair, potentially contributing to impaired cell cycle progression and elevation of senescence markers. In accordance with the analysis, we observed reduced number of AMs in aged mice, which had defective self-renewal ability and were more sensitive to the reduction of GM-CSF. Interestingly, decreased CBF{beta} was observed in the cytosol of AMs from aged mice. A similar senescence-like phenotype was also found in human AMs. Taken together, we conclude that AMs in the aged host harbor a senescence-like phenotype, potentially mediated by the activity of CBF{beta}. HighlightsO_LIscRNAseq revealed Alveolar Macrophage (AM) heterogeneity and self-renewal C_LIO_LICBF{beta} is associated with AM cell cycle and facilitate AM self-renewal C_LIO_LIAMs displayed a senescence-like phenotype during physiological Aging C_LIO_LIAging impairs CBF{beta} expression in mouse and human AMs C_LI

immunology↗

bioRxiv2021

The MuvB Complex Binds and Stabilizes Nucleosomes Downstream of the Transcription Start Site of Cell-Cycle Dependent Genes

The chromatin architecture in promoters is thought to regulate gene expression, but it remains uncertain how most transcription factors (TFs) impact nucleosome position. The MuvB TF complex regulates cell-cycle dependent gene-expression and is critical for differentiation and proliferation during development and cancer. MuvB can both positively and negatively regulate expression, but the structure of MuvB and its biochemical function are poorly understood. Here we determine the overall architecture of MuvB assembly and the crystal structure of a subcomplex critical for MuvB function in gene repression. We find that the MuvB subunits LIN9 and LIN37 function as scaffolding proteins that arrange the other subunits LIN52, LIN54 and RBAP48 for TF, DNA, and histone binding, respectively. Biochemical and structural data demonstrate that MuvB binds nucleosomes through an interface that is distinct from LIN54-DNA consensus site recognition and that MuvB increases nucleosome occupancy in a reconstituted promoter. We find in arrested cells that MuvB primarily associates with a tightly positioned +1 nucleosome near the transcription start site (TSS) of MuvB-regulated genes. These results support a model that MuvB binds and stabilizes nucleosomes just downstream of the TSS on its target promoters to repress gene-expression.

molecular biology↗