bims-imseme 2024-07-14 papers

bioRxiv. 2024 Jun 28. pii: 2024.06.23.600279. [Epub ahead of print]

NRF2-dependent regulation of the prostacyclin receptor PTGIR drives CD8 T cell exhaustion.

Michael S Dahabieh, Lisa M DeCamp, Brandon M Oswald, Susan M Kitchen-Goosen, Zhen Fu, Matthew Vos, Shelby E Compton, Joseph Longo, Kelsey S Williams, Abigail E Ellis, Amy Johnson, Ibukunoluwa Sodiya, Michael Vincent, Hyoungjoo Lee, Ryan D Sheldon, Connie M Krawczyk, Chen Yao, Tuoqi Wu, Russell G Jones.

The progressive decline of CD8 T cell effector function-also known as terminal exhaustion-is a major contributor to immune evasion in cancer. Yet, the molecular mechanisms that drive CD8 T cell dysfunction remain poorly understood. Here, we report that the Kelch-like ECH-associated protein 1 (KEAP1)-Nuclear factor erythroid 2-related factor 2 (NRF2) signaling axis, which mediates cellular adaptations to oxidative stress, directly regulates CD8 T cell exhaustion. Transcriptional profiling of dysfunctional CD8 T cells from chronic infection and cancer reveals enrichment of NRF2 activity in terminally exhausted (Tex term ) CD8 T cells. Increasing NRF2 activity in CD8 T cells (via conditional deletion of KEAP1) promotes increased glutathione production and antioxidant defense yet accelerates the development of terminally exhausted (PD-1 + TIM-3 + ) CD8 T cells in response to chronic infection or tumor challenge. Mechanistically, we identify PTGIR, a receptor for the circulating eicosanoid prostacyclin, as an NRF2-regulated protein that promotes CD8 T cell dysfunction. Silencing PTGIR expression restores the anti-tumor function of KEAP1-deficient T cells. Moreover, lowering PTGIR expression in CD8 T cells both reduces terminal exhaustion and enhances T cell effector responses (i.e. IFN-γ and granzyme production) to chronic infection and cancer. Together, these results establish the KEAP1-NRF2 axis as a metabolic sensor linking oxidative stress to CD8 T cell dysfunction and identify the prostacyclin receptor PTGIR as an NRF2-regulated immune checkpoint that regulates CD8 T cell fate decisions between effector and exhausted states.
One Sentence Summary: The KEAP1-NRF2 pathway is hyperactivated in terminally exhausted CD8 T cells and drives T cell dysfunction via transcriptional regulation of the prostacyclin receptor, Ptgir .

DOI: https://doi.org/10.1101/2024.06.23.600279

Front Transplant. 2023 ;2 1283275

Immunoregulation: the interplay between metabolism and redox homeostasis.

E Perpiñán, A Sanchez-Fueyo, N Safinia.

Regulatory T cells are fundamental for the induction and maintenance of immune homeostasis, with their dysfunction resulting in uncontrolled immune responses and tissue destruction predisposing to autoimmunity, transplant rejection and several inflammatory and metabolic disorders. Recent discoveries have demonstrated that metabolic processes and mitochondrial function are critical for the appropriate functioning of these cells in health, with their metabolic adaptation, influenced by microenvironmental factors, seen in several pathological processes. Upon activation regulatory T cells rearrange their oxidation-reduction (redox) system, which in turn supports their metabolic reprogramming, adding a layer of complexity to our understanding of cellular metabolism. Here we review the literature surrounding redox homeostasis and metabolism of regulatory T cells to highlight new mechanistic insights of these interlinked pathways in immune regulation.

Keywords: NRF2; anti-oxidants; mTOR; reactive oxygen species; regulatory T cells

DOI: https://doi.org/10.3389/frtra.2023.1283275

Exp Hematol Oncol. 2024 Jul 10. 13(1): 66

Fueling CARs: metabolic strategies to enhance CAR T-cell therapy.

Arne Van der Vreken, Karin Vanderkerken, Elke De Bruyne, Kim De Veirman, Karine Breckpot, Eline Menu.

CAR T cells are widely applied for relapsed hematological cancer patients. With six approved cell therapies, for Multiple Myeloma and other B-cell malignancies, new insights emerge. Profound evidence shows that patients who fail CAR T-cell therapy have, aside from antigen escape, a more glycolytic and weakened metabolism in their CAR T cells, accompanied by a short lifespan. Recent advances show that CAR T cells can be metabolically engineered towards oxidative phosphorylation, which increases their longevity via epigenetic and phenotypical changes. In this review we elucidate various strategies to rewire their metabolism, including the design of the CAR construct, co-stimulus choice, genetic modifications of metabolic genes, and pharmacological interventions. We discuss their potential to enhance CAR T-cell functioning and persistence through memory imprinting, thereby improving outcomes. Furthermore, we link the pharmacological treatments with their anti-cancer properties in hematological malignancies to ultimately suggest novel combination strategies.

Keywords: CAR T cells; Co-stimulus; Drug repurposing; Metabolism; Mitochondria

DOI: https://doi.org/10.1186/s40164-024-00535-1

Cell Metab. 2024 Jul 03. pii: S1550-4131(24)00235-3. [Epub ahead of print]

A Th17 cell-intrinsic glutathione/mitochondrial-IL-22 axis protects against intestinal inflammation.

The intestinal tract generates significant reactive oxygen species (ROS), but the role of T cell antioxidant mechanisms in maintaining intestinal homeostasis is poorly understood. We used T cell-specific ablation of the catalytic subunit of glutamate cysteine ligase (Gclc), which impaired glutathione (GSH) production, crucially reducing IL-22 production by Th17 cells in the lamina propria, which is critical for gut protection. Under steady-state conditions, Gclc deficiency did not alter cytokine secretion; however, C. rodentium infection induced increased ROS and disrupted mitochondrial function and TFAM-driven mitochondrial gene expression, resulting in decreased cellular ATP. These changes impaired the PI3K/AKT/mTOR pathway, reducing phosphorylation of 4E-BP1 and consequently limiting IL-22 translation. The resultant low IL-22 levels led to poor bacterial clearance, severe intestinal damage, and high mortality. Our findings highlight a previously unrecognized, essential role of Th17 cell-intrinsic GSH in promoting mitochondrial function and cellular signaling for IL-22 protein synthesis, which is critical for intestinal integrity and defense against gastrointestinal infections.

Keywords: C. rodentium; Gclc; IL-22; ROS; T cells; Th17 cells; colitis; gastrointestinal infection; glutathione; intestinal barrier; mitochondrial function

DOI: https://doi.org/10.1016/j.cmet.2024.06.010

Nature. 2024 Jul 10.

A liver immune rheostat regulates CD8 T cell immunity in chronic HBV infection.

Miriam Bosch, Nina Kallin, Sainitin Donakonda, Jitao David Zhang, Hannah Wintersteller, Silke Hegenbarth, Kathrin Heim, Carlos Ramirez, Anna Fürst, Elias Isaac Lattouf, Martin Feuerherd, Sutirtha Chattopadhyay, Nadine Kumpesa, Vera Griesser, Jean-Christophe Hoflack, Juliane Siebourg-Polster, Carolin Mogler, Leo Swadling, Laura J Pallett, Philippa Meiser, Katrin Manske, Gustavo P de Almeida, Anna D Kosinska, Ioana Sandu, Annika Schneider, Vincent Steinbacher, Yan Teng, Julia Schnabel, Fabian Theis, Adam J Gehring, Andre Boonstra, Harry L A Janssen, Michiel Vandenbosch, Eva Cuypers, Rupert Öllinger, Thomas Engleitner, Roland Rad, Katja Steiger, Annette Oxenius, Wan-Lin Lo, Victoria Klepsch, Gottfried Baier, Bernhard Holzmann, Mala K Maini, Ron Heeren, Peter J Murray, Robert Thimme, Carl Herrmann, Ulrike Protzer, Jan P Böttcher, Dietmar Zehn, Dirk Wohlleber, Georg M Lauer, Maike Hofmann, Souphalone Luangsay, Percy A Knolle.

Chronic hepatitis B virus (HBV) infection affects 300 million patients worldwide1,2, in whom virus-specific CD8 T cells by still ill-defined mechanisms lose their function and cannot eliminate HBV-infected hepatocytes3-7. Here we demonstrate that a liver immune rheostat renders virus-specific CD8 T cells refractory to activation and leads to their loss of effector functions. In preclinical models of persistent infection with hepatotropic viruses such as HBV, dysfunctional virus-specific CXCR6+ CD8 T cells accumulated in the liver and, as a characteristic hallmark, showed enhanced transcriptional activity of cAMP-responsive element modulator (CREM) distinct from T cell exhaustion. In patients with chronic hepatitis B, circulating and intrahepatic HBV-specific CXCR6+ CD8 T cells with enhanced CREM expression and transcriptional activity were detected at a frequency of 12-22% of HBV-specific CD8 T cells. Knocking out the inhibitory CREM/ICER isoform in T cells, however, failed to rescue T cell immunity. This indicates that CREM activity was a consequence, rather than the cause, of loss in T cell function, further supported by the observation of enhanced phosphorylation of protein kinase A (PKA) which is upstream of CREM. Indeed, we found that enhanced cAMP-PKA-signalling from increased T cell adenylyl cyclase activity augmented CREM activity and curbed T cell activation and effector function in persistent hepatic infection. Mechanistically, CD8 T cells recognizing their antigen on hepatocytes established close and extensive contact with liver sinusoidal endothelial cells, thereby enhancing adenylyl cyclase-cAMP-PKA signalling in T cells. In these hepatic CD8 T cells, which recognize their antigen on hepatocytes, phosphorylation of key signalling kinases of the T cell receptor signalling pathway was impaired, which rendered them refractory to activation. Thus, close contact with liver sinusoidal endothelial cells curbs the activation and effector function of HBV-specific CD8 T cells that target hepatocytes expressing viral antigens by means of the adenylyl cyclase-cAMP-PKA axis in an immune rheostat-like fashion.

DOI: https://doi.org/10.1038/s41586-024-07630-7

bioRxiv. 2024 Jun 28. pii: 2024.06.26.600763. [Epub ahead of print]

Transient inhibition of type I interferon enhances CD8 + T cell stemness and vaccine protection.

Benjamin J Broomfield, Chin Wee Tan, Raymond Z Qin, Brigette C Duckworth, Carolina Alvarado, Lennard Dalit, Jinjin Chen, Liana Mackiewicz, Hiromi Muramatsu, Marc Pellegrini, Kelly L Rogers, Woohyun J Moon, Stephen L Nutt, Melissa J Davis, Norbert Pardi, Verena C Wimmer, Joanna R Groom.

Developing vaccines that promote CD8 + T cell memory is a challenge for infectious disease and cancer immunotherapy. TCF-1 + stem cell-like memory T (T SCM ) cells are important determinants of long-lived memory. Yet, the developmental requirements for T SCM formation are unclear. Here, we identify the temporal window for type I interferon (IFN-I) receptor (IFNAR) blockade to drive T SCM cell generation. T SCM cells were transcriptionally distinct and emerged from a transitional precursor of exhausted (T PEX ) cellular state concomitant with viral clearance. T SCM differentiation correlated with T cell retention within the lymph node paracortex, due to increased CXCR3 chemokine abundance which disrupted gradient formation. These affects were due a counterintuitive increase in IFNψ, which controlled cell location. Combining IFNAR inhibition with mRNA-LNP vaccination promoted specific T SCM differentiation and enhanced protection against chronic infection. These finding propose a new approach to vaccine design whereby modulation of inflammation promotes memory formation and function.
HIGHLIGHTS: Early, transient inhibition of the type I interferon (IFN) receptor (IFNAR) during acute viral infection promotes stem cell-like memory T (T SCM ) cell differentiation without establishing chronic infection. T SCM and precursor of exhausted (T PEX ) cellular states are distinguished transcriptionally and by cell surface markers. Developmentally, T SCM cell differentiation occurs via a transition from a T PEX state coinciding with viral clearance. Transient IFNAR blockade increases IFNψ production to modulate the ligands of CXCR3 and couple T SCM differentiation to cell retention within the T cell paracortex of the lymph node. Specific promotion of T SCM cell differentiation with nucleoside-modified mRNA-LNP vaccination elicits enhanced protection against chronic viral challenge.

DOI: https://doi.org/10.1101/2024.06.26.600763

Eur J Immunol. 2024 Jul 09. e2451018

Regulation of IFN-γ production by ZFP36L2 in T cells is time-dependent.

Nordin D Zandhuis, Aurélie Guislain, Abeera Popalzij, Sander Engels, Branka Popović, Martin Turner, Monika C Wolkers.

CD8+ T cells kill target cells by releasing cytotoxic molecules and proinflammatory cytokines, such as TNF and IFN-γ. The magnitude and duration of cytokine production are defined by posttranscriptional regulation, and critical regulator herein are RNA-binding proteins (RBPs). Although the functional importance of RBPs in regulating cytokine production is established, the kinetics and mode of action through which RBPs control cytokine production are not well understood. Previously, we showed that the RBP ZFP36L2 blocks the translation of preformed cytokine encoding mRNA in quiescent memory T cells. Here, we uncover that ZFP36L2 regulates cytokine production in a time-dependent manner. T cell-specific deletion of ZFP36L2 (CD4-cre) had no effect on T-cell development or cytokine production during early time points (2-6 h) of T-cell activation. In contrast, ZFP36L2 specifically dampened the production of IFN-γ during prolonged T-cell activation (20-48 h). ZFP36L2 deficiency also resulted in increased production of IFN-γ production in tumor-infiltrating T cells that are chronically exposed to antigens. Mechanistically, ZFP36L2 regulates IFN-γ production at late time points of activation by destabilizing Ifng mRNA in an AU-rich element-dependent manner. Together, our results reveal that ZFP36L2 employs different regulatory nodules in effector and memory T cells to regulate cytokine production.

Keywords: Cytokines; Molecular immunology; Posttranscriptional regulation; T cells; Tumor immunology

DOI: https://doi.org/10.1002/eji.202451018