Biology subjects

Panse, I.

Publications and source records attributed to Panse, I..

4 recordsLinked to original sources

bioRxiv2025

Stable characteristics of intrapopulation heterogeneity in virus-specific Th1 cells during chronic viral challenge infection

Virus-specific CD4+ T cells typically undergo T helper (Th) 1 differentiation and contribute to a type 1 immune response in infection with lymphocytic choriomeningitis virus (LCMV). Using this model pathogen, we performed an in-depth analysis of the quantitative expression stability of the Th1 key transcription factor T-bet. Previously, it was shown that virus-specific Th1 cells arising in acute infections expressed T-bet at distinct intensities and maintained their T-bet expression differences after viral clearance as memory cells for weeks in the steady state. However, it was unclear whether differential T-bet expression was associated with heterogeneity inside the Th1 population and if the quantitative T-bet memory, particularly of those cells expressing T-bet at low levels, could withhold the strong and continuous stimulation present during chronic infection. Using T-bet-ZsGreen reporter mice, virus-specific Th1 cells were characterized phenotypically at protein, RNA, and DNA/chromatin accessibility levels. The Th1 cells arising during acute LCMV Armstrong infection showed a continuous spectrum of T-bet expression, ranging from cells with very high T-bet to cells with low T-bet. Even though the cells with low T-bet expression clearly possessed Th1 characteristics, they additionally showed certain Tfh-like features at protein and RNA level. When virus-specific Th1 cells were sorted according to T-bet-ZsGreen reporter expression intensity, adoptively transferred, and rechallenged by infecting the host animals with the chronic Clone 13 strain of LCMV, they maintained quantitative differences in T-bet reporter and IFN-{gamma} expression levels. A subpopulation of the progeny of the former T-betlow cells still showed a mild Tfh-associated phenotype. Independent of their past and present T-bet expression level, all virus-reactive CD4+ T cells acquired phenotypic signs of exhaustion as characterized by upregulation of PD-1, LAG3, and TOX and vast absence of effector cytokine co-expression in the chronic infection environment. Collectively, our findings highlight the heterogeneity of T-bet+ antiviral CD4+ T cells and the stability of quantitative differences in individual virus-specific CD4+ T cells during chronic viral challenge infection.

immunology↗

bioRxiv2022

Plasticity and lineage commitment of individual Th1 cells are determined by stable T-bet expression quantities

T helper 1 (Th1) cell identity is defined by the expression of the lineage-defining transcription factor T-bet. Here, we examine the influence of T-bet expression heterogeneity on subset plasticity by leveraging cell sorting of distinct in vivo-differentiated Th1 cells based on their quantitative expression of T-bet and interferon-{gamma}. Heterogeneous T-bet expression states were regulated by virus-induced type-I interferons and were stably maintained even after secondary viral infection. Exposed to Th2-polarizing conditions, the sorted subpopulations exhibited graded levels of plasticity: T-bet quantities were inversely correlated with the ability to express the Th2 lineage-specifying transcription factor GATA-3 and Th2 cytokines. Reprogramed Th1 cells acquired graded, but stable mixed Th1+2 phenotypes with a hybrid epigenetic landscape. Continuous presence of T-bet in differentiated Th1 cells was essential to ensure Th1 cell stability. Thus, innate cytokine signals regulate Th1 cell plasticity via an individual cell-intrinsic rheostat to enable T cell subset adaptation to subsequent challenges. HIGHLIGHTSO_LIType-I interferons triggered by infection determine T-bet expression states in Th1 cells C_LIO_LIT-bet and IFN-{gamma} expression states indicate the plasticity of individual Th1 cells C_LIO_LIIndividual T-bet expression states and plasticity persist after secondary infection C_LIO_LIReprogramming yields stable Th1+2 phenotypes and a mixed epigenetic landscape C_LI

immunology↗

bioRxiv2021

Biomechanics and Myofibrillar Alignment Enhance Contractile Development and Reproducibility in Stem Cell Derived Cardiac Muscle

Human pluripotent stem cell derived cardiomyocytes (hPSC-CMs) allow novel investigations of human cardiac disease, but disorganized mechanics and immaturity of hPSC-CMs on two-dimensional (2D) surfaces have been hurdles for efficient and reproducible study of these cells. Here, we developed a platform of micron-scale 2D cardiac tissues (M2DCTs) to precisely control biomechanics in arrays of thousands of purified, independently contracting cardiac muscle strips in 2D. By defining geometry and workload in M2DCTs in this reductionist platform that does not incorporate other cell types, we show that myofibrillar alignment and auxotonic contractions at physiologic workload critically drive maturation of cardiac contractile function, calcium handling, and electrophysiology. Additionally, the organized biomechanics in this system facilitates rapid and automated extraction of contractile kinetic parameters from brightfield microscopy images, increasing the reproducibility and throughput of pharmacologic testing. Finally, we show that M2DCTs enable precise and efficient dissection of contractile kinetics in cardiomyopathy disease models.

cell biology↗

bioRxiv2020

Autophagy in T cells from aged donors is maintained by spermidine, and correlates with function and vaccine responses

Older adults are at high risk for infectious diseases such as the recent COVID-19 and vaccination seems to be the only long-term solution to the pandemic. While most vaccines are less efficacious in older adults, little is known about the molecular mechanisms that underpin this. Autophagy, a major degradation pathway and one of the few processes known to prevent aging, is critical for the maintenance of immune memory in mice. Here, we show induction of autophagy is specifically induced in human vaccine-induced antigen-specific T cells in vivo. Reduced IFN{gamma} secretion by vaccine-induced T cells in older vaccinees correlates with low autophagy. We demonstrate in human cohorts that levels of the endogenous autophagy-inducing metabolite spermidine, fall with age and supplementing it in vitro recovers autophagy and T cell function. Finally, our data show that endogenous spermidine maintains autophagy via the translation factor eIF5A and transcription factor TFEB. With these findings we have uncovered novel targets and biomarkers for the development of anti-aging drugs for human T cells, providing evidence for the use of spermidine in improving vaccine immunogenicity in the aged human population.

physiology↗