Biology subjects

Andris, F.

Publications and source records attributed to Andris, F..

5 recordsLinked to original sources

bioRxiv2026

TCR Signal Strength and Eomes Coordinate CD8⁺ T Cell Fate and Antitumor Immunity in Hepatocellular Carcinoma

Hepatocellular carcinoma (HCC) poses a persistent barrier to effective immunotherapy, in part due to the emergence of exhausted CD8+ T cells. Using a hydrodynamic, autochthonous HCC model based on Sleeping Beauty-mediated delivery of oncogenic drivers and defined OVA-derived antigens, we could manipulate antigen affinity under physiological priming conditions. With this system, we examined how TCR signal strength and the transcription factor Eomesodermin (Eomes) shape CD8+ T cell fate in vivo. High-affinity stimulation supported robust effector differentiation and the formation of tissue-resident memory T cells (Trm), resulting in early tumor control. In contrast, low-affinity stimulation induced elevated Eomes expression and favored rapid transition toward an exhausted (Tex) phenotype. Genetic repression of Eomes enhanced Trm differentiation in high-affinity CD8+ T cells and delayed tumor relapse, whereas ectopic Eomes expression accelerated exhaustion and led to earlier tumor recurrence. Under low-affinity conditions, Eomes deficiency increased the Trm-to-Tex ratio but remained insufficient to restore effective antitumor immunity, indicating that weak TCR engagement imposes constraints that cannot be overcome by Eomes loss alone. These findings reveal that the strength of TCR engagement shapes CD8+ T cell fate in HCC, while Eomes selectively biases this process toward exhaustion at the expense of effector and resident memory programs, ultimately influencing the durability of tumor control. SynopsisThis study reveals that the strength of T-cell receptor signaling fundamentally steers whether CD8+ T cells in liver cancer become durable tumor-fighting cells or slip into exhaustion, pinpointing Eomes as a key factor that pushes cells toward dysfunction. By uncovering how antigen affinity and Eomes jointly shape antitumor immunity, the work offers new conceptual and therapeutic avenues for improving the persistence and effectiveness of immunotherapies in hepatocellular carcinoma.

immunology↗

bioRxiv2022

Drosophila cap-binding protein eiF4EHP promotes translation via a 3'UTR-dependent mechanism under hypoxia and contributes to fruit fly adaptation to oxygen variations

Hypoxia induces profound modifications in gene expression program enabling eukaryotic cells to adapt to lowered ATP supply resulting from the blockade of oxidative phosphorylation. One major consequence of oxygen deprivation is the massive repression of protein synthesis, leaving a limited set of mRNAs to be translated. D. melanogaster is strongly resistant to oxygen fluctuations, however the mechanisms allowing specific mRNA to be translated in hypoxia are still unknown. Here, we show that Ldh mRNA encoding lactate dehydrogenase is highly translated in hypoxia by a mechanism involving its 3 untranslated region. Furthermore, we identified the cap-binding protein eiF4HP as a main factor involved in 3UTR-dependent translation under hypoxia. In accordance with this observation, we show that eiF4EHP is necessary for Drosophila development under low oxygen concentrations and contributes to Drosophila mobility after hypoxic challenge. Altogether, our data bring new insight into mechanisms contributing to Drosophila adaptation to oxygen variations.

molecular biology↗

bioRxiv2021

The oxygen sensor Prolyl hydroxylase domain 2 regulates the in vivo suppressive capacity of regulatory T cells

The oxygen sensor PHD2 (prolyl hydroxylase domain 2) plays an important role in cell hypoxia adaptation by regulating the stability of HIF proteins (HIF1 and HIF2) in numerous cell types including T lymphocytes. The role of oxygen sensor on immune cells, in particular on regulatory T cell (Treg) function, has not been fully elucidated. The purpose of our study was to evaluate the role of PHD2 in the regulation of Treg phenotype and function. We demonstrate herein that selective ablation of PHD2 expression in Treg (PHD2{Delta}Treg mice) leads to a spontaneous systemic inflammatory syndrome, as evidenced by weight loss, development of a rectal prolapse, splenomegaly, shortening of the colon and elevated expression of IFN-{gamma} in the mesenteric lymph nodes, intestine and spleen. PHD2 deficiency in Tregs led to an increased number of activated CD4 conventional T cells expressing a Th1-like effector phenotype. Concomitantly, the expression of innate-type cytokines such as Il1b, Il12a, Il12b and Tnfa was found to be elevated in peripheral (gut) tissues and spleen. PHD2{Delta}Treg mice also displayed an enhanced sensitivity to DSS-induced colitis and to toxoplasmosis, suggesting that PHD2-deficient Tregs did not efficiently control inflammatory response in vivo, in particular those characterized by IFN-{gamma} production. Further analysis revealed that Treg dysregulation was largely prevented in PHD2-HIF2 (PHD2-HIF2{Delta}Treg mice), but not in PHD2-HIF1 (PHD2-HIF1{Delta}Treg mice) double KOs, suggesting an important and possibly selective role of the PHD2-HIF2 axis in the control of Treg function. Finally, the transcriptomic analysis of PHD2-deficient Tregs identified the STAT1 pathway as a target of the PHD2-HIF2 axis in regulatory T cell phenotype and in vivo function.

immunology↗

bioRxiv2020

Long-term homeostatic T cell proliferation is driven by AMPK-dependent regulation of oxygen reactive species

The AMP-activated kinase (AMPK) is a major energy sensor metabolic enzyme that is activated early during T cell immune responses but its role in the generation of effector T cells is still controversial.Using both in vitro and in vivo models of T cell proliferation, we show herein that AMPK is dispensable for early TCR signaling and short-term proliferation but required for sustained long-term T cell proliferation and effector / memory T cell survival. In particular, AMPK promoted accumulation of effector / memory T cells in competitive homeostatic proliferation settings. Transplantation of AMPK-deficient hematopoïetic cells into allogeneic host recipients led to a reduced graft-versus-host disease, further bolstering a role for AMPK in the expansion and pathogenicity of effector T cells.Mechanistically, AMPK expression enhances the mitochondrial membrane potential of T cells, limits reactive oxygen species (ROS) production, and resolves ROS-mediated toxicity. Moreover, dampening ROS production alleviates the proliferative defect of AMPK-deficient T cells, therefore indicating a role for an AMPK-mediated ROS control of T cell fitness.Competing Interest StatementThe authors have declared no competing interest.View Full Text

immunology↗

bioRxiv2019

Multiple environmental signaling pathways control the differentiation of RORγt-expressing regulatory T cells

ROR{gamma}t-expressing Tregs form a specialized subset of intestinal CD4+ Foxp3+ cells which is essential to maintain gut homeostasis and tolerance to commensal microbiota. Recently, c-Maf emerged as a critical factor in the regulation of ROR{gamma}t expression in Tregs. However, aside from c-Maf signaling, the signaling pathways involved in the differentiation of ROR{gamma}t+ Tregs and their possible interplay with c-Maf in this process are largely unknown. We show that ROR{gamma}t+ Treg development is controlled by positive as well as negative signals. Along with c-Maf signaling, signals derived from a complex microbiota, as well as IL-6/STAT3- and TGF-{beta}-derived signals act in favor of ROR{gamma}t+ Treg development. Ectopic expression of c-Maf did not rescue ROR{gamma}t expression in STAT3-deficient Tregs, indicating the presence of additional effectors downstream of STAT3. Moreover, we show that an inflammatory IFN-{gamma}/STAT1 signaling pathway acts as a negative regulator of ROR{gamma}t+ Treg differentiation in a c-Maf independent fashion.\n\nThese data thus argue for a complex integrative signaling network that finely tunes ROR{gamma}t expression in Tregs. The finding that type 1 inflammation impedes ROR{gamma}t+ Treg development even in the presence of an active IL-6/STAT3 pathway further suggests a dominant negative effect of STAT1 over STAT3 in this process.

immunology↗