Biology subjects

Patil, V. S.

Publications and source records attributed to Patil, V. S..

3 recordsLinked to original sources

bioRxiv2025

A distinct subset of stem-cell memory is poised for the cytotoxicity program in CD4+ T cells in humans.

The peripheral CD4+ T-cells with cytolytic potential (CD4-CTLs) have been detected in several diseases, including infectious diseases and various cancers. They form the component of protective immune response and are shown to be enriched in the effector memory expressing CD45RA (TEMRA) in humans. However, the lack of understanding about their lineage, molecular characters, and cytolytic potential in comparison to CD8-CTLs has restricted their utility. Thus, in this study, by parallelly analysing the CD4-CTLs and CD8-CTLs, we demonstrate that they are indistinguishable for the cytolytic program, with both showing similar gene expression profile and T cell antigen-receptor (TCR) clonal expansion in humans. Further, using an integrative multi-omics analysis combining the transcriptome, TCR repertoire, and open chromatin profile of CD4+ naive (CD4-TN) and memory T-cell subsets, we discovered a distinct stem-cell memory subset (TSCM-CTL) that is pre-committed to cytolytic program that shared significant TCR clonotypes with expanded CD4-CTL-effectors. Further, through an in vitro differentiation model, we developed CD4+ T-cells with cytolytic potential (iCD4-CTLs) from CD4-TN cells that showed gradual and progressive acquisition of cytolytic program, exhibiting progressive chromatin accessibility at cytotoxicity-associated genes. Of particular interest was the property of iCD4-CTLs that co-expressed longevity-associated genes along with cytotoxicity-associated genes, hence generating long-lived CD4-CTL-effectors. Overall, the process of generation of iCD4-CTLs from CD4-TN, deciphered the molecular signatures of early commitment to the cytotoxicity program. Together, our study advocates for exploring both CD4-CTLs and CD8-CTLs for vaccine development, vaccine efficacy testing, as well as immunotherapies and cell-based therapies for precision medicine. TeaserIntegrative multi-omics analysis of CD4+ T cell subsets revealed the cytolytic potential of CD4-TEMRA cells in comparison to CD8-TEMRA and their origin from stem-cell memory.

immunology↗

bioRxiv2025

JNK2 pathway in colonocytes enhances gut barrier integrity in response to microbial acetate.

Weaning involves a nutritional shift from fat-rich milk to carbohydrate-based solid food, reshaping metabolism, microbiota, and gut immune tolerance. While dairy remains a component of the human diet beyond weaning, the impact of continued milk supplementation on gut epithelial homeostasis remains poorly understood. Here, using a mouse model, we show that continued milk-based feeding post-weaning promotes intestinal barrier function by enriching the commensal bacterium Dubosiella newyorkensis, which produces acetate to activate epithelial JNK2 signaling. This pathway enhances barrier integrity and suppresses inflammation induced by mild Dextran Sodium Sulphate (DSS) treatment. In contrast, feeding a lard-based high-fat diet or transient pharmacologic inhibition of JNK2 induces epithelial P38 activation, resulting in barrier disruption and inflammation. Importantly, the beneficial effects of milk were observed only if initiated during the weaning period, when the microbiome is in a metastable transitional state. Initiation of the same intervention two weeks after weaning led to P38 activation and inflammatory responses. These findings highlight the microbiome-dependent, stage-specific effects of diet and underscore the importance of early-life nutritional interventions for long-term gut health.

physiology↗

bioRxiv2023

Single-cell transcriptome and TCR analysis of human Cytomegalovirus (hCMV)-specific T cell memory reveals effector and pre-effectors of CD8+ and CD4+ cytotoxic T cells

BackgroundLatent human Cytomegalovirus (hCMV) infection can pose a serious threat of reactivation and disease occurrence in immune-compromised individuals. Though, T cells are at the core of the protective immune response to hCMV infection, a detailed characterization of different T cell subsets involved in hCMV immunity is lacking. ResultsHere, in an unbiased manner, we characterized over 8000 hCMV-reactive peripheral memory T cells isolated from seropositive human donors, at a single-cell resolution by analyzing their single-cell transcriptomes paired with the T cell antigen receptor (TCR) repertoires. The hCMV-reactive T cells were highly heterogeneous and consisted of different developmental and functional memory T cell subsets such as, long-term memory precursors and effectors, T helper-17, T regulatory cells (TREGs) and cytotoxic T lymphocytes (CTLs) of both CD4 and CD8 origin. The hCMV-specific TREGs, in addition to being enriched for molecules known for their suppressive functions, showed enrichment for the interferon response signature gene sets. The hCMV-specific CTLs were of two types, the pre-effector and effector-like. The co-clustering of hCMV-specific CD4-CTLs and CD8-CTLs in both pre-effector as well as effector clusters suggest shared transcriptomic signatures between them. The huge TCR clonal expansion of cytotoxic clusters suggest a dominant role in protective immune response to CMV. ConclusionsThe study uncovers the heterogeneity in the hCMV-specific memory T cells reveling many functional subsets with potential implications in better understanding of hCMV-specific T cell immunity. The data presented can serve as a knowledge base for designing vaccines and therapeutics.

immunology↗