Biology subjects

Sturmlechner, I.

Publications and source records attributed to Sturmlechner, I..

4 recordsLinked to original sources

bioRxiv2025

Antigen-specific Th17 T cells offset the age-related decline in durable T cell immunity

Older adults are susceptible to infections, in part due to waning of immune memory. To determine mechanisms that determine long-lasting versus short-term immunity, we examined varicella zoster virus (VZV) vaccination as a model system. We contrasted VZV antigen-specific T cells several years after vaccination in adults who had been vaccinated at young (<20 years) or older age (>50 years) with a live-attenuated vaccine that confers durable protection only when given at young age, or with an adjuvanted VZV component vaccine that elicits effective, long-lasting immunity in older adults. CD8+ T cells were highly sensitive to age-related changes showing T cell subset shifts, loss in TCR diversity and reduced stem-like features while gaining NK-like signatures without evidence for cellular senescence or exhaustion. VZV-specific CD4+ T cells were largely resilient to age and maintained phenotypic and TCR diversity. Immunization of older adults with the adjuvanted VZV vaccine did not reverse age-associated defects in CD8+ T cells. Instead, it selectively improved the functionality of VZV-specific Th17 CD4+ T cells and prevented their acquisition of Treg features, likely as consequence of lipid metabolic pathways. Collectively, our data indicate that effective vaccination in older adults is supported by the generation of a durable, antigen-specific CD4+ Th17 population that resists mis-differentiation into Tregs and that compensates for age-related defects in CD8+ T cells. One sentence summaryAging primarily impairs the CD8+ T cell VZV vaccine response, while effective VZV vaccination in older adults induces antigen-specific Th17 CD4+ T cells to compensate for aging defects.

immunology↗

bioRxiv2024

Aging trajectories of memory CD8+ T cells differ by their antigen specificity

Memory T cells are a highly dynamic and heterogeneous population that is maintained by cytokine-driven homeostatic proliferation interspersed with episodes of antigen-mediated expansion and contraction which affect their functional state and their durability. This heterogeneity complicates studies on the impact of aging on global human memory cells, specifically, it is unclear how aging drives memory T cell dysfunction. Here, we used chronic infection with Epstein-Barr virus (EBV) to assess the influence of age on memory states at the level of antigen-specific CD8+ T cells. We find that in young adults (<40 years), EBV-specific CD8+ T cells assume preferred differentiation states depending on their peptide specificity. By age >65-years, different T cell specificities had undergone largely distinct aging trajectories, which had in common a loss in adaptive and a gain in innate immunity signatures. No evidence was seen for cellular senescence or exhaustion. While naive/stem-like EBV-specific T cells disappeared with age, T cell diversity of EBV-specific memory cells did not change or even increased. In summary, by controlling for antigen specificity we uncover age-associated shifts in gene expression and TCR diversity that have implications for optimizing vaccination strategies and adoptive T cell therapy.

immunology↗

bioRxiv2022

HD-PTP/PTPN23 hypomorphic mice display lipodystrophy

Endosomal Sorting Complexes Required for Transport (ESCRTs) drive reverse topology membrane remodeling events including the formation of intralumenal vesicles within multivesicular bodies, the budding of retroviruses from the plasma membrane, and the scission of the cytokinetic bridge. It has been difficult to study the physiological relevance of this machinery in mammals because many contributing components are essential for viability. To bypass this problem we used combinations of knockout (-), hypomorphic (H) and wildtype (+) alleles to generate a series of mice with a gradual reduction of HD-PTP (product of PTPN23), an ESCRT-associated protein known to cause embryonic lethality when fully depleted. Whereas PTPN23-/H mice died shortly after birth, PTPN23H/H mice developed into adulthood but had reduced size, lipodystrophy, and shortened lifespan. Analysis of 14-day inguinal adipose tissue indicated reduced expression of adipogenesis markers, and PTPN23 knockout preadipocytes similarly display reduced adipogenesis in vitro. Defects in insulin-stimulated signaling were apparent in differentiated PTPN23 knockout adipocytes and PTPN23H/H inguinal adipose tissue in vitro, correlating with reduced levels of insulin signaling hallmarks observed in adult PTPN23H/H inguinal adipose tissue in vivo. Whereas the ESCRT machinery have been suggested to downregulate signaling, these results indicate that HD-PTP promotes insulin-induced signaling in, as well as differentiation of, inguinal adipose tissue. These results revealed unexpected roles for HD-PTP in promoting fat accumulation in mammalian cells through supporting insulin signaling, adipogenesis, and lipid droplet formation.

cell biology↗

bioRxiv2022

Transfer learning of an in vivo-derived senescence signature identifies conserved and tissue-specific senescence across species and diverse pathologies

Senescent cells (SnCs) contribute to normal tissue development and repair but accumulate with aging where they are implicated in a number of pathologies and diseases. Despite their pathological role and therapeutic interest, SnC phenotype and function in vivo remains unclear due to the challenges in identifying and isolating these rare cells. Here, we developed an in vivo-derived senescence gene expression signature using a model of the foreign body response (FBR) fibrosis in a p16Ink4a-reporter mouse, a cell cycle inhibitor commonly used to identify SnCs. We identified stromal cells (CD45-CD31- CD29+) as the primary p16Ink4a expressing cell type in the FBR and collected the cells to produce a SnC transcriptomic signature with bulk RNA sequencing. To computationally identify SnCs in bulk and single-cell data sets across species and tissues, we used this signature with transfer learning to generate a SnC signature score (SenSig). We found senescent pericyte and cartilage-like fibroblasts in newly collected single cell RNAseq (scRNASeq) data sets of murine and human FBR suggesting populations associated with angiogenesis and secretion of fibrotic extracellular matrix, respectively. Application of the senescence signature to human scRNAseq data sets from idiopathic pulmonary fibrosis (IPF) and the basal cell carcinoma microenvironment identified both conserved and tissue-specific SnC phenotypes, including epithelial-derived basaloid and endothelial cells. In a wound healing model, ligand-receptor signaling prediction identified putative interactions between SnC SASP and myeloid cells that were validated by immunofluorescent staining and in vitro coculture of SnCs and macrophages. Collectively, we have found that our SenSig transfer learning strategy from an in vivo signature outperforms in vitro-derived signatures and identifies conserved and tissue-specific SnCs and their SASP, independent of p16Ink4a expression, and may be broadly applied to elucidate SnC identity and function in vivo.

bioengineering↗