Biology subjects

Fitzgerald-Bocarsly, P.

Publications and source records attributed to Fitzgerald-Bocarsly, P..

8 recordsLinked to original sources

bioRxiv2026

A transitional senescence program drives inflammatory monocyte state expansion in aging humans

Dysfunctional monocyte states contribute to age-related pathologies and systemic inflammation. However, the gene regulatory networks governing the transition to these states remain unknown. Here we used bulk and single-cell multidimensional integrative profiling to reveal previously uncharacterized monocyte state transitions during human aging. We show that a transient senescent-like population arising from classical CD14++ CD16- monocytes drives the accumulation of an inflammatory monocyte state in aging humans. This senescence-associated transition is orchestrated by the master senescence regulator AP-1, which acts on a pre-established chromatin landscape to rewire the monocyte transcription factor (TF) network and activate both senescence- and age-associated inflammatory transcriptional programs. Through integration with clinical transcriptomic datasets, we demonstrate that senescent-like and aged monocytes are transcriptionally primed toward sepsis-associated states. Overall, our study provides the core gene-regulatory principles underlying a senescent-like transitional state in monocytes and identifies AP-1 as an attractive target to modulate systemic inflammation in age and disease.

systems biology↗

bioRxiv2025

Senescent CD8+ T Effector Memory Cells are Functionally Impaired, Enriched in Aging and Disease, and a Barrier to Immunotherapy

Senescent cells play important roles in various biological processes that promote fitness and health, however, their timely elimination by immune cells is critical to maintain tissue homeostasis and prevent disease. Despite this, senescent cells progressively accumulate systemically with age, suggesting that certain immune cells also become senescent and dysfunctional during aging. Supporting this, we previously demonstrated that CD8 T cells, immune cells capable of targeting senescent cells, increasingly develop characteristics of senescence with advancing age in humans. Here, we further characterized the senescence state of human SA-{beta}Gal-expressing CD8 T effector cells, their functional capabilities, and their involvement in aging and disease. Single-cell RNA sequencing revealed that SA-{beta}Gal-expressing CD8 T cells with unique transcriptional signatures develop in all stages of T cell differentiation, including in effector memory (EM) T cells. SA-{beta}Gal-expressing CD8 TEM cells expressed various classical markers of senescence and were significantly impaired in their ability to proliferate, produce cytokines, and eliminate senescent human stromal cells, compared to CD8 TEM cells with low SA-{beta}Gal activity. Gene signatures of senescent SA-{beta}Gal-expressing CD8 TEM cells were enriched in CD8 T cells from older human donors, patients with age-related disorders, cancer, and smokers. Furthermore, our results demonstrate that T cell senescence is distinct from and dominant over T cell exhaustion, limiting the response of CD8 TEM cells to immunotherapy. Collectively, our study demonstrates that the senescence state impairs the functions of CD8 TEM cells and reveals the involvement of senescent and dysfunctional CD8 TEM cells in aging, disease, exposure to toxins, and responses to immunotherapy.

cell biology↗

bioRxiv2025

Epigenetic mechanisms regulating CD8+ T cell senescence in aging humans

Aging leads to the decline of immunity, rendering the elderly susceptible to infection and disease. In the CD8+ T cell compartment, aging leads to a substantial increase of cells with high levels of senescence-associated {beta}-galactosidase activity (SA-{beta}Gal) and other senescence characteristics, including a pro-inflammatory transcriptome and impaired proliferative potential. Using senescent cell isolation coupled with multiomic profiling, here we characterized the epigenetic mechanisms regulating CD8+ T cell senescence in a cohort of younger and older donors. High levels of SA-{beta}Gal activity defined changes to global transcriptomes and chromatin accessibility landscapes, with a minor effect of age. Widespread enhancer remodeling was required for the repression of functional CD8+ T cell genes and upregulation of inflammatory and secretory pathway genes. Mechanistically, the senescence program in CD8+ T cells was controlled by chromatin state-specific transcription factor (TF) networks whose composition was largely insensitive to donor age. Pharmacological inhibition of TF network nodes AP1, KLF5, and RUNX2 modulated the transcriptional output, demonstrating the feasibility of TF network perturbation as an approach to modulate CD8+ T cell senescence. Further, CD8+ T cell senescence gene signatures faithfully predicted refractoriness to chimeric antigen receptor (CAR) T-cell therapy in a cohort of diffuse large B cell lymphomas and were highly enriched in the transcriptomes of peripheral CD8+ T cells of individuals with active systemic lupus erythematosus. Collectively, our findings demonstrate the potential of multiomic profiling in identifying key regulators of senescence across cell types and suggest a critical role of senescent CD8+ T cells in disease progression.

genomics↗

bioRxiv2024

Metabolic Deficiencies Underlie Plasmacytoid Dendritic Cell Exhaustion After Viral Infection

Type I Interferons (IFN-I) are central to host protection against viral infections1. While any cell can produce IFN-I, Plasmacytoid Dendritic Cells (pDCs) make greater quantities and more varieties of these cytokines than any other cell type2. However, following an initial burst of IFN- I, pDCs lose their exceptional IFN-I production capacity and become "exhausted", a phenotype that associates with enhanced susceptibility to secondary infections3-5. Despite this apparent cost for the host, pDC exhaustion is conserved across multiple species and viral infections, but the underlying mechanisms and the potential evolutionary advantages are not well understood. Here we characterize pDC exhaustion and demonstrate that it is associated with a reduced capacity of pDCs to engage both oxidative and glycolytic metabolism. Mechanistically, we identify lactate dehydrogenase B (LDHB) as a novel positive regulator of pDC IFN-I production in mice and humans, show that LDHB deficiency is associated with suppressed IFN-I production, pDC metabolic capacity, and viral control following a viral infection, and demonstrate that preservation of LDHB expression is sufficient to partially restore exhausted pDC function in vitro and in vivo. Furthermore, restoring LDHB in vivo in exhausted pDCs increased IFNAR dependent infection- associated pathology. Therefore, our work identifies a novel and conserved mechanism for balancing immunity and pathology during viral infections, while also providing insight into the highly preserved but previously unexplained phenomenon of pDC exhaustion.

immunology↗

bioRxiv2023

Interferon epsilon restricts Zika virus infection in the female reproductive tract

Interferon {varepsilon} (IFN{varepsilon}) is a unique type I IFN that has been implicated in host defense against sexually transmitted infections (STIs). Zika virus (ZIKV), an emerging pathogen, can infect the female reproductive tract (FRT) and cause devastating diseases, particularly in pregnant women. How IFN{varepsilon} contributes to protection against ZIKV infection in vivo is unknown. Here, we show that IFN{varepsilon} plays a critical role in host protection against vaginal ZIKV infection in mice. We found that IFN{varepsilon} was expressed not only by epithelial cells in the FRT, but also by certain immune and other cells at baseline or after exposure to viruses or specific TLR agonists. IFN{varepsilon}-deficient mice exhibited abnormalities in the epithelial border and underlying tissue in the cervicovaginal tract, and these defects were associated with increased susceptibility to vaginal, but not subcutaneous ZIKV infection. IFN{varepsilon}-deficiency resulted in an increase in magnitude, duration, and depth of ZIKV infection in the FRT. Critically, intravaginal administration of recombinant IFN{varepsilon} protected Ifn{varepsilon}-/- mice and highly susceptible Ifnar1-/-mice against vaginal ZIKV infection, indicating that IFN{varepsilon} was sufficient to provide protection even in the absence of signals from other type I IFNs and in an IFNAR1-independent manner. Our findings reveal a potentially critical role for IFN{varepsilon} in mediating protection against transmission of ZIKV in the context of sexual contact. SignificanceInterferon {varepsilon} (IFN{varepsilon}), a unique Type I IFN that is highly expressed in the epithelium of the female reproductive tract (FRT), is thought to protect the host against sexually transmitted infections (STIs) but the mechanism of action is not defined. Zika virus (ZIKV), a causative agent for preterm birth and other severe diseases in pregnant women, can be spread through vaginal transmission. Here, we show that mice lacking the Ifn{varepsilon} gene have abnormal epithelial development and tissue architecture in the cervicovaginal tract. The role of IFN{varepsilon} in protecting host against ZIKV is FRT-specific and is independent of IFNAR1 signaling. Our findings suggest potential preventive strategies based on harnessing mucosal immunity against STIs.

immunology↗

bioRxiv2022

TLR4 signaling in presence of HIV-induced activation enhances programmed death ligand-1 expression on human plasmacytoid dendritic cells and modulates their function

Human Plasmacytoid dendritic cells (pDC) only comprise a minute fraction of human mononuclear leukocytes, but are important anti-viral responders that mediate both innate as well as adaptive immune responses. Persistent activation of pDC enhances HIV pathogenesis by promoting immune suppressive mechanisms such as T regulatory cells. It is therefore important to identify the sources of pDC activation in the context of HIV infection. HIV-associated disruption of gut mucosa associated lymphoid tissue introduces normal flora-lipopolysaccharide (LPS) into systemic circulation, which exacerbates HIV-induced immune activation. We report here that pDC are capable of mediating functional TLR4 signaling upon LPS stimulation, and that pDC of HIV-infected individuals have enhanced TLR4 expression compared to healthy individuals. How TLR4 signaling affects pDC function in HIV infection has not been examined before. Hence we examined the influence of TLR4 signaling in presence of HIVstimulation on pDC and found that it not only potentiated HIV-induced activation but also strongly up-regulated Programmed death ligand-1 (PD-L1) expression and Interleukin-6 synthesis. TLR4 signaling specifically up-regulated PD-L1 expression on activated pDC in presence of HIV stimulation. LPS and HIV co-stimulated pDC demonstrated enhanced migratory potential and repressed T cell proliferation. Together, these results suggest that in the setting of HIV infection enhancement of pDC immune suppressive mechanisms such as PD-L1 may be an outcome of HIV-associated immune activation potentiated by TLR4 signaling.

immunology↗

bioRxiv2020

Conclusive Identification of Senescent T Cells Reveals Their Abundance in Aging Humans

Aging leads to a progressive functional decline of the immune system, which renders the elderly increasingly susceptible to disease and infection. The degree to which immune cell senescence contributes to this functional decline, however, remains unclear since methods to accurately identify and isolate senescent immune cells are missing. By measuring senescence-associated {beta}-galactosidase activity, a hallmark of senescent cells, we demonstrate here that healthy humans develop senescent T lymphocytes in peripheral blood with advancing age. Particularly senescent CD8+ T cells increased in abundance with age, ranging from 30% of the total CD8+ T cell population in donors in their 20s and reaching levels of 64% in donors in their 60s. Senescent CD8+ T cell populations displayed features of telomere dysfunction-induced senescence as well as p16-mediated senescence, developed in various T cell differentiation states and established gene expression signatures consistent with the senescence state observed in other cell types. On the basis of our results we propose that cellular senescence of T lymphocytes is a major contributing factor to the observed decline of immune cell function with advancing age and that immune cell senescence, therefore, plays a significant role in the increased susceptibility of the elderly to age-associated diseases and infection.

cell biology↗

bioRxiv2020

HDAC inhibitors decrease TLR7/9-mediated human plasmacytoid dendritic cell activation by interfering with IRF-7 and NF-қB signaling

Histone deacetylase inhibitors (HDACi) are epigenome modulating molecules that target histone and non-histone proteins and have been successfully used to target many types of cancer and immunological disorders. While HDACis effects on nuclear histone deacetylases are well characterized, their effect on non-nuclear, cytoplasmic molecules requires further investigation. In the current study we characterized the effects of class I/II HDACi, specifically, TSA, MS-275, and SAHA, on plasmacytoid dendritic cell (pDC) biology upon viral activation via the TLR7/9 pathway. TSA, MS-275, and SAHA, down-modulated the induction of IFN- and TNF- upon Influenza A virus (IAV; TLR7 signaling) and Herpes Simplex 1 (HSV-1; TLR9 signaling) stimulation in primary pDC. The HDACi inhibitory effect was more prominent for IAV-mediated responses than for HSV-1. While IFN- induction was not associated with inhibition of IRF-7 upregulation in the presence of TSA or MS-275, IRF-7 upregulation was affected by SAHA, but only for IAV. Furthermore, TSA, but not MS-275, inhibited TLR7/9-induced expression of maturation markers, CD40, and CD86, but not CD40. In addition, HDACi treatment increased virally-induced shedding of CD62L. Mechanistically, TSA, MS-275, SAHA significantly decreased early IRF-7 and NF-{kappa}B nuclear translocation, which was preceded by a decline in phosphorylation of IRF-7 at Ser477/479 and NF-{kappa}B p-p65, except for MS-275. In summary, we propose that broad HDACi, but not class I HDACi, treatment can negatively impact early TLR7/9-mediated signaling, namely, the disruption of IRF-7 and NF-{kappa}B activation and translocation that lead to deleterious effects on pDC function.

immunology↗