Epigenetic analysis of human γδ T lymphocytes

Human γδ T-cells have emerged as key players in diverse immune responses both in health and disease. Such a dynamic functional diversity of cells is controlled at various levels of epi)genetic regulation in an orchestrated manner. However, a comprehensive overview of epigenetic mechanisms dictating human γδ T-cell development, regulation and molecular function is largely missing. The present thesis aims at elucidating the epigenetic landscape of human γδ T-cells by mainly two distinct approaches. In a first approach based on in vitro culture, the NKG2D ligand expression and release, and its further implications on NKG2D receptor expression by epigenetic inhibitors such as histone deacetylase inhibitor valproic acid, a drug widely used in the clinic, was studied. The modulation of NKG2D receptor expression and function of γδ T cells in co-culture with pancreatic carcinoma and prostate carcinoma tumor cell lines were addressed. Additionally, the effect on functional responses of γδ T-cells upon treatment with valproic acid provided new insight into γδ T-cell subset-specific responses. Specifically, valproic acid induced changes in molecular and cellular responses of human γδ T-cells, specifically by enhanced expression of the non-secretory form of IL-4, regulation of cell death and induction of global histone acetylation (H3K9ac) [...

An innovative Deep Learning Based Approach for Accurate Agricultural Crop Price Prediction

Accurate prediction of agricultural crop prices is a crucial input for decision-making by various stakeholders in agriculture: farmers, consumers, retailers, wholesalers, and the Government. These decisions have significant implications including, most importantly, the economic well-being of the farmers. In this paper, our objective is to accurately predict crop prices using historical price information, climate conditions, soil type, location, and other key determinants of crop prices. This is a technically challenging problem, which has been attempted before. In this paper, we propose an innovative deep learning based approach to achieve increased accuracy in price prediction. The proposed approach uses graph neural networks (GNNs) in conjunction with a standard convolutional neural network (CNN) model to exploit geospatial dependencies in prices. Our approach works well with noisy legacy data and produces a performance that is at least 20% better than the results available in the literature. We are able to predict prices up to 30 days ahead. We choose two vegetables, potato (stable price behavior) and tomato (volatile price behavior) and work with noisy public data available from Indian agricultural markets.Comment: 9 pages, 3 figures, 3 table

PrimeQA: The Prime Repository for State-of-the-Art Multilingual Question Answering Research and Development

The field of Question Answering (QA) has made remarkable progress in recent years, thanks to the advent of large pre-trained language models, newer realistic benchmark datasets with leaderboards, and novel algorithms for key components such as retrievers and readers. In this paper, we introduce PRIMEQA: a one-stop and open-source QA repository with an aim to democratize QA re-search and facilitate easy replication of state-of-the-art (SOTA) QA methods. PRIMEQA supports core QA functionalities like retrieval and reading comprehension as well as auxiliary capabilities such as question generation.It has been designed as an end-to-end toolkit for various use cases: building front-end applications, replicating SOTA methods on pub-lic benchmarks, and expanding pre-existing methods. PRIMEQA is available at : https://github.com/primeqa

Histone Deacetylase Inhibitor Modulates NKG2D Receptor Expression and Memory Phenotype of Human Gamma/Delta T Cells Upon Interaction With Tumor Cells

The functional plasticity and anti-tumor potential of human γδ T cells have been widely studied. However, the epigenetic regulation of γδ T-cell/tumor cell interactions has been poorly investigated. In the present study, we show that treatment with the histone deacetylase inhibitor Valproic acid (VPA) significantly enhanced the expression and/or release of the NKG2D ligands MICA, MICB and ULBP-2, but not ULBP-1 in the pancreatic carcinoma cell line Panc89 and the prostate carcinoma cell line PC-3. Under in vitro tumor co-culture conditions, the expression of full length and the truncated form of the NKG2D receptor in γδ T cells was significantly downregulated. Furthermore, using a newly established flow cytometry-based method to analyze histone acetylation (H3K9ac) in γδ T cells, we showed constitutive H3K9aclow and inducible H3K9achigh expression in Vδ2 T cells. The detailed analysis of H3K9aclow Vδ2 T cells revealed a significant reversion of TEMRA to TEM phenotype during in vitro co-culture with pancreatic ductal adenocarcinoma cells. Our study uncovers novel mechanisms of how epigenetic modifiers modulate γδ T-cell differentiation during interaction with tumor cells. This information is important when considering combination therapy of VPA with the γδ T-cell-based immunotherapy for the treatment of certain types of cancer

Immunotherapy With Human Gamma Delta T Cells—Synergistic Potential of Epigenetic Drugs?

Epigenetics has emerged as one of the fastest growing concepts, adding more than 45 new publications every day, spreading through various fields ( 1). Conrad Waddington coined the term “epigenetics” in 1942; however, a multitude of definitions has been endorsed by different researchers. In essence, Waddington’s definition of “epigenetics” and its redefinition by Holiday is at the heart of cellular function. Hence, it is obvious that epigenetic regulation plays a central role also in the specification, differentiation, and functional plasticity of T lymphocytes ( 2). T-cell fate decision in progenitor cells, functional CD4 T-cell plasticity, CD8 T-cell differentiation, but also T-cell memory, are all substantially governed by epigenetic mechanisms (3–7). Here, we focus on the current development of drugs targeting major pathways of epigenetic regulation and their possible impact on γδ T-cell multifunctionality. We aim to develop concepts of how some of these approaches might help to improve the efficacy of γδ T-cell-based immunotherapies

Contemplating dichotomous nature of gamma delta T cells for immunotherapy

$\gamma$$\delta$ T cells are unconventional T cells, distinguished from $\alpha$$\beta$ T cells in a number of functional properties. Being small in number compared to $\alpha$$\beta$ T cells, $\gamma$$\delta$ T cells have surprised us with their pleiotropic roles in various diseases. $\gamma$$\delta$ T cells are ambiguous in nature as they can produce a number of cytokines depending on the (micro) environmental cues and engage different immune response mechanisms, mainly due to their epigenetic plasticity. Depending on the disease condition, $\gamma$$\delta$ T cells contribute to beneficial or detrimental response. In this review, we thus discuss the dichotomous nature of $\gamma$$\delta$ T cells in cancer, neuroimmunology and infectious diseases. We shed light on the importance of equal consideration for systems immunology and personalized approaches, as exemplified by changes in metabolic requirements. While providing the status of immunotherapy, we will assess the metabolic (and other) considerations for better outcome of $\gamma$$\delta$ T cell-based treatments

Vitamin C supports conversion of human γδ T cells into FOXP3-expressing regulatory cells by epigenetic regulation.

Human γδ T cells are potent cytotoxic effector cells, produce a variety of cytokines, and can acquire regulatory activity. Induction of FOXP3, the key transcription factor of regulatory T cells (Treg), by TGF-β in human Vγ9 Vδ2 T cells has been previously reported. Vitamin C is an antioxidant and acts as multiplier of DNA hydroxymethylation. Here we have investigated the effect of the more stable phospho-modified Vitamin C (pVC) on TGF-β-induced FOXP3 expression and the resulting regulatory activity of highly purified human Vγ9 Vδ2 T cells. pVC significantly increased the TGF-β-induced FOXP3 expression and stability and also increased the suppressive activity of Vγ9 Vδ2 T cells. Importantly, pVC induced hypomethylation of the Treg-specific demethylated region (TSDR) in the FOXP3 gene. Genome-wide methylation analysis by Reduced Representation Bisulfite Sequencing additionally revealed differentially methylated regions in several important genes upon pVC treatment of γδ T cells. While Vitamin C also enhances effector functions of Vγ9 Vδ2 T cells in the absence of TGF-β, our results demonstrate that pVC potently increases the suppressive activity and FOXP3 expression in TGF-β-treated Vγ9 Vδ2 T cells by epigenetic modification of the FOXP3 gen

DataSheet_1_Impact of SARS-CoV-2 vaccination on systemic immune responses in people living with HIV.pdf

Despite the development of vaccines, which protect healthy people from severe and life-threatening Covid-19, the immunological responses of people with secondary immunodeficiencies to these vaccines remain incompletely understood. Here, we investigated the humoral and cellular immune responses elicited by mRNA-based SARS-CoV-2 vaccines in a cohort of people living with HIV (PLWH) receiving anti-retroviral therapy. While antibody responses in PLWH increased progressively after each vaccination, they were significantly reduced compared to the HIV-negative control group. This was particularly noteworthy for the Delta and Omicron variants. In contrast, CD4+ Th cell responses exhibited a vaccination-dependent increase, which was comparable in both groups. Interestingly, CD4+ T cell activation negatively correlated with the CD4 to CD8 ratio, indicating that low CD4+ T cell numbers do not necessarily interfere with cellular immune responses. Our data demonstrate that despite the lower CD4+ T cell counts SARS-CoV-2 vaccination results in potent cellular immune responses in PLWH. However, the reduced humoral response also provides strong evidence to consider PLWH as vulnerable group and suggests subsequent vaccinations being required to enhance their protection against COVID-19.</p