Murine iNKT cells are depleted by liver damage via activation of P2RX7

Invariant natural killer T cells (iNKT) constitute up to 50% of liver lymphocytes and contribute to immunosurveillance as well as pathogenesis of the liver. Systemic activation of iNKT cells induces acute immune-mediated liver injury. However, how tissue damage events regulate iNKT cell function and homeostasis remains unclear. We found that specifically tissue-resident iNKT cells in liver and spleen express the tissue-damage receptor P2RX7 and the P2RX7-activating ectoenzyme ARTC2. P2RX7 expression restricted formation of iNKT cells in the liver suggesting that liver iNKT cells are actively restrained under homeostatic conditions. Deliberate activation of P2RX7 in vivo by exogenous NAD resulted in a nearly complete iNKT cell ablation in liver and spleen in a P2RX7-dependent manner. Tissue damage generated by acetaminophen-induced liver injury reduced the number of iNKT cells in the liver. The tissue-damage-induced iNKT cell depletion was driven by P2RX7 and localized to the site of injury, as iNKT cells in the spleen remained intact. The depleted liver iNKT cells reconstituted only slowly compared to other lymphocytes such as regulatory T cells. These findings suggest that tissue-damage-mediated depletion of iNKT cells acts as a feedback mechanism to limit iNKT cell-induced pathology resulting in the establishment of a tolerogenic environment

Blimp-1 Rather Than Hobit Drives the Formation of Tissue-Resident Memory CD8+ T Cells in the Lungs

Tissue-resident memory CD8+ T (TRM) cells that develop in the epithelia at portals of pathogen entry are important for improved protection against re-infection. CD8+ TRM cells within the skin and the small intestine are long-lived and maintained independently of circulating memory CD8+ T cells. In contrast to CD8+ TRM cells at these sites, CD8+ TRM cells that arise after influenza virus infection within the lungs display high turnover and require constant recruitment from the circulating memory pool for long-term persistence. The distinct characteristics of CD8+ TRM cell maintenance within the lungs may suggest a unique program of transcriptional regulation of influenza-specific CD8+ TRM cells. We have previously demonstrated that the transcription factors Hobit and Blimp-1 are essential for the formation of CD8+ TRM cells across several tissues, including skin, liver, kidneys, and the small intestine. Here, we addressed the roles of Hobit and Blimp-1 in CD8+ TRM cell differentiation in the lungs after influenza infection using mice deficient for these transcription factors. Hobit was not required for the formation of influenza-specific CD8+ TRM cells in the lungs. In contrast, Blimp-1 was essential for the differentiation of lung CD8+ TRM cells and inhibited the differentiation of central memory CD8+ T (TCM) cells. We conclude that Blimp-1 rather than Hobit mediates the formation of CD8+ TRM cells in the lungs, potentially through control of the lineage choice between TCM and TRM cells during the differentiation of influenza-specific CD8+ T cells

Industry in the 5th Environmental Outlook. Background information and final conclusions on the future development of environmental pressure (emissions) due tot industrial production in the Netherlands

Het rapport geeft een integraal overzicht van alle gegevens, aannames, en modellen die zijn gebruikt door de doelgroep industrie van het Laboratorium voor Afvalstoffen en Emissies (LAE) ten behoeve van de 5e Nationale Milieuverkenning (MV5). Het rapport beschrijft de verwachte ontwikkelingen in milieudruk door de industrie tot 2020 onder invloed van ontwikkelingen in industriele productie, energiegebruik en vastgesteld milieubeleid, in de context van het European Coordination (EC) en het Global Competition (GC) scenario. Emissieprognoses worden afgezet tegen emissietrends in de periode 1980-heden. Daarmee wordt een integraal overzicht gegeven van de belangrijkste determinanten in de ontwikkeling van de milieudruk door de industrie over de periode 1980-2020. Uit de studie volgt, dat bij het vastgestelde milieubeleid het energiegebruik en de CO2 emissie ten gevolge van industriele productie blijft toenemen. Hierbij wordt ook de CO2 emissie die vrijkomt in de energiesector, door energieomzetting ten behoeve van de industrie, toegerekend aan de industrie. De toename van de emissie van het broeikasgas CO2 wordt deels geneutraliseerd door een sterk dalende emissie (-80%) van fluorhoudende broeikasgassen, onder invloed van enkele specifieke bedrijfsmaatregelen. De emissie van NOx, SO2, VOS en fijn stof neemt verder af. De doelstellingen voor NOx, SO2 en VOS emissies voor 2010 blijven echter buiten bereik. Met voorliggend rapport wordt het industrie aandeel in het project MV5 kwaliteitgeborgd afgerond.This RIVM study presents information on the present and future development of environmental pressure (here emissions) due tot industrial production in the Netherlands. Results were - strongly aggregated - also presented in the 5th Environmental Outlook. We studied developments in production levels, energy use and emissions of Dutch industry and the effect of environmental policy measures, in the period 1980-2020. We used monitoring data for the period 1980-1998 en two scenarios (Global Competition and European Coordination) for the subsequent 1998-2020 period. It is concluded, that future CO2 emissions due to industrial production will continue to increase, that emissions of fluorinated (Kyoto) gasses will strongly decrease and that emissions of NOx, SO2, VOS en fine particles will continue to decrease. Yet, current environmental policy is insufficient to meet national Dutch emission targets of NOx, SO2, VOS in 2010.RIV

Memory CD8⁺ T cell heterogeneity is primarily driven by pathogen-specific cues and additionally shaped by the tissue environment

SummaryFactors that govern the complex formation of memory T cells are not completelyunderstood. A better understanding of thedevelopment of memory Tcell hetero-geneity is however required to enhance vaccination and immunotherapy ap-proaches. Here we examined the impact of pathogen- and tissue-specific cueson memory CD8+T cell heterogeneity using high-dimensional single-cell mass cy-tometry and a tailored bioinformatics pipeline. We identified distinct populationsof pathogen-specific CD8+T cells that uniquely connected to a specific pathogenor associated to multiple types of acute and persistent infections. In addition, thetissue environment shaped the memory CD8+T cell heterogeneity, albeit to alesser extent than infection. The programming of memory CD8+T cell differenti-ation during acute infection is eventually superseded by persistent infection.Thus, the plethora of distinct memory CD8+T cell subsets that arise upon infec-tion is dominantly sculpted by the pathogen-specific cues and further shaped by the tissue environment.</p

T RM maintenance is regulated by tissue damage via P2RX7

Tissue-resident memory T cells (TRM) are noncirculating immune cells that contribute to the first line of local defense against reinfections. Their location at hotspots of pathogen encounter frequently exposes TRM to tissue damage. This history of danger-signal exposure is an important aspect of TRM-mediated immunity that has been overlooked so far. RNA profiling revealed that TRM from liver and small intestine express P2RX7, a damage/danger-associated molecular pattern (DAMP) receptor that is triggered by extracellular nucleotides (ATP, NAD+). We confirmed that P2RX7 protein was expressed in CD8+ TRM but not in circulating T cells (TCIRC) across different infection models. Tissue damage induced during routine isolation of liver lymphocytes led to P2RX7 activation and resulted in selective cell death of TRM P2RX7 activation in vivo by exogenous NAD+ led to a specific depletion of TRM while retaining TCIRC The effect was absent in P2RX7-deficient mice and after P2RX7 blockade. TCR triggering down-regulated P2RX7 expression and made TRM resistant to NAD-induced cell death. Physiological triggering of P2RX7 by sterile tissue damage during acetaminophen-induced liver injury led to a loss of previously acquired pathogen-specific local TRM in wild-type but not in P2RX7 KO T cells. Our results highlight P2RX7-mediated signaling as a critical pathway for the regulation of TRM maintenance. Extracellular nucleotides released during infection and tissue damage could deplete TRM locally and free niches for new and infection-relevant specificities. This suggests that the recognition of tissue damage promotes persistence of antigen-specific over bystander TRM in the tissue niche

OX40 agonism enhances PD-L1 checkpoint blockade by shifting the cytotoxic T cell differentiation spectrum

Immune checkpoint therapy (ICT) has the power to eradicate cancer, but the mechanisms that determine effective therapy-induced immune responses are not fully understood. Here, using high-dimensional single-cell profiling, we interrogate whether the landscape of T cell states in the peripheral blood predict responses to combinatorial targeting of the OX40 costimulatory and PD-1 inhibitory pathways. Single-cell RNA sequencing and mass cytometry expose systemic and dynamic activation states of therapy-responsive CD4+ and CD8+ T cells in tumor-bearing mice with expression of distinct natural killer (NK) cell receptors, granzymes, and chemokines/chemokine receptors. Moreover, similar NK cell receptor-expressing CD8+ T cells are also detected in the blood of immunotherapy-responsive cancer patients. Targeting the NK cell and chemokine receptors in tumor-bearing mice shows the functional importance of these receptors for therapy-induced anti-tumor immunity. These findings provide a better understanding of ICT and highlight the use and targeting of dynamic biomarkers on T cells to improve cancer immunotherapy.</p