Biology subjects

Pillai, S. S.

Publications and source records attributed to Pillai, S. S..

3 recordsLinked to original sources

bioRxiv2025

A unified network systems approach uncovers a core novel program underlying T follicular helper cell differentiation

T follicular helper (Tfh) cells are central to the adaptive immune response and exhibit remarkable functional diversity and plasticity. The complex nature of Tfh cell populations, inconsistent findings across experimental systems and potential differences across species have fueled ongoing debate regarding core regulatory pathways that govern Tfh differentiation. Many studies have experimentally investigated individual proteins and circuits involved in Tfh differentiation in limited contexts, each providing only a partial understanding of the process. To address this, we adopted a novel multi-scale network systems approach that incorporates both regulatory and protein-protein interactions. Our approach integrates diverse data types, captures regulation across multiple levels of immune system organization, and recapitulates known drivers. Further, we discover a core Tfh gene set that is conserved across tissue types and disease contexts, and is consistent across data modalities - bulk, single-cell and spatial. While components of this set have been individually reported, a novel aspect of our work lies in the discovery, characterization, and connectivity of this core signature using a single unbiased approach. Using this method, we also uncover a novel function of IL-12, a molecule with reported conflicting functions, in the regulation of Tfh differentiation. Notably, we find that, in both humans and mice, IL-12 is permissive for the differentiation of Tfh precursors, but blocks subsequent differentiation into GC Tfh cells. Overall, this work elucidates novel networks with unexplored roles in governing Tfh cell differentiation across species and tissues, paving the way for novel -therapeutic interventions.

immunology↗

bioRxiv2025

Na/K-ATPase Signaling in Adipocytes Promotes Atherosclerosis

BACKGROUNDAdipocyte dysfunction is closely associated with oxidative stress and chronic inflammation, which contribute to systemic metabolic disturbances and atherosclerosis. We previously identified Na/K-ATPase (NKA) 1 as a signal transducer that activates Src family kinases and promotes oxidative stress and inflammation in various cell types, including adipocytes and macrophages. NaKtide, a peptide inhibitor of NKA signaling, has been shown to reduce systemic oxidative stress and inflammation in vivo. Here, we investigated the role of adipocyte-specific NKA signaling in atherosclerosis. METHODSAdipocyte-specific NaKtide (Adipo-NaKtide) was delivered to Apoe-/- mice using a lentiviral vector under the adiponectin promoter. The mice were then fed a Western Diet (WD) for 12 weeks to induce atherosclerosis and then assessed for atherosclerotic plaque burden the aortic arch and at the level of the aortic sinus. Inflammatory and oxidative stress markers were analyzed in adipose tissue and plasma. RESULTSAdipo-NaKtide reduced atherosclerotic plaque area by 67% in the aortic arch and 47% in the aortic sinus. CD68+ macrophage and -SMA+ smooth muscle cell content in the aortic sinus were decreased by 45% and 53%, respectively. These vascular improvements were accompanied by dampened adipose tissue inflammation and oxidative stress, improved glucose tolerance, and lowered systemic inflammation. CONCLUSIONSThese findings highlight a critical contributing role for adipocyte NKA signaling in atherosclerosis, suggesting an important endocrine and/or paracrine influence of adipose tissue on large artery atherogenesis, and supporting the therapeutic potential of targeting NKA in cardiometabolic disease.

molecular biology↗

bioRxiv2021

Network-based integration of epigenetic landscapes unveils molecular programs underlying human T follicular helper cell differentiation

T follicular helper (Tfh) cells play a critical role in T-dependent humoral immune responses. While genetic programs controlling Tfh cell differentiation have been extensively studied using murine models, studies in humans have been hampered by the lack of a robust in vitro differentiation system for Tfh cells. We characterized epigenomic landscapes across stages of Tfh cell differentiation in a healthy human tonsil using ATAC-Seq and CUT&RUN for selected histone modifications. We combined these epigenomic datasets and integrated them with the reference human protein interactome using a novel network propagation approach. Our approach uncovered subnetworks integral to Tfh cell differentiation. These subnetworks captured known Tfh cell drivers to a greater extent than conventional gene-centric analyses would, and also revealed novel modules that may be required for Tfh cell differentiation. We find that human Tfh cell subnetworks are functionally associated with specific immune signaling cascades including cytokine receptor driven pathways. Analyses of transcriptomic data revealed that in addition to these immune pathways being significantly dysregulated in severe COVID-19, the corresponding Tfh cell subnetworks are also transcriptionally perturbed to a similar extent. This provides a molecular mechanistic basis for the previously observed impaired Tfh cell differentiation and loss of germinal centers in severe COVID-19.

immunology↗