New Insights Into the Regulation of γδ T Cells by BTN3A and Other BTN/BTNL in Tumor Immunity

Recent findings in the immunology field have pointed out the emergent role of butyrophilins/butyrophilin-like molecules (BTN/BTNL in human, Btn/Btnl in mouse) in the modulation of γδ T cells. As long as the field develops exponentially, new relationships between certain γδ T cell subsets, on one hand, and their BTN/BTNL counterparts mainly present on epithelial and tumor cells, on the other, are described in the scientific literature. Btnl1/Btnl6 in mice and BTNL3/BTNL8 in humans regulate the homing and maturation of Vγ7+ and Vγ4+ T cells to the gut epithelium. Similarly, Skint-1 has shown to shape the dendritic epidermal T cells repertoire and their activation levels in mice. We and others have identified BTN3A proteins are the key mediators of phosphoantigen sensing by human Vγ9Vδ2 T cells. Here, we first synthesize the modulation of specific γδ T cell subsets by related BTN/BTNL molecules, in human and mice. Then, we focus on the role of BTN3A in the activation of Vγ9Vδ2 T cells, and we highlight the recent advances in the understanding of the expression, regulation, and function of BTN3A in tumor immunity. Hence, recent studies demonstrated that several signals induced by cancer cells or their microenvironment can regulate the expression of BTN3A. Moreover, antibodies targeting BTN3A have shown in vitro and in vivo efficacy in human tumors such as acute myeloid leukemia or pancreatic cancer. We thus finally discuss how these findings could help develop novel γδ T cell-based immunotherapeutical approaches

XAB2 promotes Ku eviction from single-ended DNA double-strand breaks independently of the ATM kinase

Replication-associated single-ended DNA double-strand breaks (seDSBs) are repaired predominantly through RAD51-mediated homologous recombination (HR). Removal of the non-homologous end-joining (NHEJ) factor Ku from resected seDSB ends is crucial for HR. The coordinated actions of MRE11-CtIP nuclease activities orchestrated by ATM define one pathway for Ku eviction. Here, we identify the pre-mRNA splicing protein XAB2 as a factor required for resistance to seDSBs induced by the chemotherapeutic alkylator temozolomide. Moreover, we show that XAB2 prevents Ku retention and abortive HR at seDSBs induced by temozolomide and camptothecin, via a pathway that operates in parallel to the ATM-CtIP-MRE11 axis. Although XAB2 depletion preserved RAD51 focus formation, the resulting RAD51-ssDNA associations were unproductive, leading to increased NHEJ engagement in S/G2 and genetic instability. Overexpression of RAD51 or RAD52 rescued the XAB2 defects and XAB2 loss was synthetically lethal with RAD52 inhibition, providing potential perspectives in cancer therapy.publishedVersio

Imidazole propionate is increased in diabetes and associated with dietary patterns and altered microbial ecology

Microbiota-host-diet interactions contribute to the development of metabolic diseases. Imidazole propionate is a novel microbially produced metabolite from histidine, which impairs glucose metabolism. Here, we show that subjects with prediabetes and diabetes in the MetaCardis cohort from three European countries have elevated serum imidazole propionate levels. Furthermore, imidazole propionate levels were increased in subjects with low bacterial gene richness and Bacteroides 2 enterotype, which have previously been associated with obesity. The Bacteroides 2 enterotype was also associated with increased abundance of the genes involved in imidazole propionate biosynthesis from dietary histidine. Since patients and controls did not differ in their histidine dietary intake, the elevated levels of imidazole propionate in type 2 diabetes likely reflects altered microbial metabolism of histidine, rather than histidine intake per se. Thus the microbiota may contribute to type 2 diabetes by generating imidazole propionate that can modulate host inflammation and metabolism

Evidence of a causal and modifiable relationship between kidney function and circulating trimethylamine N-oxide

The host-microbiota co-metabolite trimethylamine N-oxide (TMAO) is linked to increased cardiovascular risk but how its circulating levels are regulated remains unclear. We applied "explainable" machine learning, univariate, multivariate and mediation analyses of fasting plasma TMAO concentration and a multitude of phenotypes in 1,741 adult Europeans of the MetaCardis study. Here we show that next to age, kidney function is the primary variable predicting circulating TMAO, with microbiota composition and diet playing minor, albeit significant, roles. Mediation analysis suggests a causal relationship between TMAO and kidney function that we corroborate in preclinical models where TMAO exposure increases kidney scarring. Consistent with our findings, patients receiving glucose-lowering drugs with reno-protective properties have significantly lower circulating TMAO when compared to propensity-score matched control individuals. Our analyses uncover a bidirectional relationship between kidney function and TMAO that can potentially be modified by reno-protective anti-diabetic drugs and suggest a clinically actionable intervention for decreasing TMAO-associated excess cardiovascular risk

Expression et fonction de LIGHT et HVEM, membres de la superfamille des TNF/TNFR, sur les lymphocytes B normaux et leucémiques (LLC-B)

Les membres de la superfamille des TNF/TNFR jouent un rôle important dans de nombreux processus biologiques, en participant à des réponses variées telles que la prolifération, l organogenèse, l apoptose ou l inflammation. Au cours de ma thèse, nous avons pu évaluer l expression et le rôle de HVEM, membre de la superfamille des TNFR, et son ligand LIGHT sur les lymphocytes B normaux et pathologiques. Ces travaux nous ont permis de mettre en évidence une coopération entre LIGHT et CD40L pour induire l expression de LIGHT à la surface des lymphocytes B, ainsi que pour la prolifération de ces cellules. Par la suite, nous avons analysé le rôle de HVEM sur les cellules B pathologiques, en choisissant la leucémie lymphoïde chronique (LLC-B). Nous avons montré un effet pro-apoptotique de HVEM sur les LLC-B et avons décrit certains des mécanismes moléculaires impliqués dans cette mort cellulaire, dont l activation des caspases, la dépolarisation de la membrane mitochondriale, ainsi que l augmentation d expression de Bax et FADD. Par ailleurs, nous avons constaté que la stimulation par HVEM entraîne la production de chimiokines pro-inflammatoires, telle que l IL-8, par les LLC-B. Ainsi, HVEM représenterait une cible thérapeutique potentielle, en agissant par son action directe sur l apoptose des cellules de LLC-B, et en mobilisant le microenvironnement cellulaire contre le clone tumoral.TNF/TNFR family members play a crucial role in several biological processes, regulating various responses such as proliferation, organogenesis, apoptosis or inflammation. During my thesis, we evaluated the expression and the function of HVEM, a TNFR member and its ligand LIGHT on normal and leukemic B lymphocytes. We enlightened a cooperation between LIGHT and another TNF member, CD40L, for the induction of LIGHT protein at the membrane, and for B-cell proliferation. Then, we focused on HVEM role on haematopoietic malignancy, particularly B-CLL (chronic lymphocytic leukemia). Our results reveal a proapoptotic effect of HVEM on B-CLL cells and we described the mechanisms involved in this cell death, including caspase activation, loss of mitochondrial membrane potential, and increased Bax and FADD expression. Moreover, we found that HVEM stimulation increased inflammatory chemokine production by B-CLL cells, particularly significant amounts of IL-8. Taken together, these results suggest that HVEM could represent a potential therapeutic target by a direct apoptotic effect on B-CLL cells, and by recruiting immune system against leukemic cells.AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocSudocFranceF

Highly effective NK cells are associated with good prognosis in patients with metastatic prostate cancer

Clinical outcome of patients with metastatic prostate cancer (mPC) at diagnosis is heterogeneous and unpredictable; thus alternative treatments such as immunotherapy are investigated. We retrospectively analyzed natural killer (NK) cells by flow cytometry in peripheral blood from 39 mPC patients, with 5 year-follow-up, and their correlation with time to castration resistance (TCR) and overall survival (OS). In parallel, NK functionality was carried out against prostate tumor cell lines, analyzed for the expression of NK cell ligands, to identify the receptors involved in PC recognition. NK cells from patients with longer TCR and OS displayed high expression of activating receptors and high cytotoxicity. The activating receptors NKp30 and NKp46 were the most obvious predictive markers of OS and TCR in a larger cohort of mPC patients (OS: p= 0.0018 and 0.0009; TCR: p= 0.007 and < 0.0001 respectively, log-rank test). Importantly, blocking experiments revealed that NKp46, along with NKG2D and DNAM-1 and, to a lesser extent NKp30, were involved in prostate tumor recognition by NK cells. These results identify NK cells as potential predictive biomarkers to stratify patients who are likely to have longer castration response, and pave the way to explore therapies aimed at enhancing NK cells in mPC patients

A role for HVEM, but not lymphotoxin-beta receptor, in LIGHT-induced tumor cell death and chemokine production

The TNF member LIGHT also known as TL4 or TNFSF14) can play a major role in cancer control via its two receptors; it induces tumor cell death through lymphotoxin-P receptor (LT-beta R) and ligation to the herpes virus entry mediator (HVEM) amplifies the immune response. By studying the effect of LIGHT in the transcriptional profile of a lymphoid malignancy, we found that HVEM, but not LT-beta R, stimulation induces a significant increase in the expression of chemokine genes such as IL-8, and an unexpected upregulation of apoptotic genes. This had functional consequences, since LIGHT, or HVEM mAb, thus far known to costimulate T- and B-cell activation, induced chronic lymphocytic leukemia cell death. Many of the mediators involved were identified here, with an apoptotic pathway as demonstrated by caspases activation, decrease in mitochondrial membrane potential, upregulation of the pro-apoptotic protein Bax, but also a role of TRAIL. Moreover, HVEM induced endogenous TNF-alpha production and TNF-alpha enhanced HVEM-mediated cell death. HVEM function was mainly dependent on LIGHT, since other ligands like HSV-glycoprotein D and B and T lymphocyte attenuator were essentially ineffective. in conclusion, we describe a novel, as yet unknown killing effect of LIGHT through HVEM on a lymphoid malignancy, and combined with induction of chemokine release this may represent an additional tool to boost cancer immunotherap

BTN2A, a New Immune-Checkpoint Targeting Vg9Vd2 T Cell Cytotoxicity

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