Impact of Mycobacterium tuberculosis Glycolipids on the CD4+ T Cell-Macrophage Immunological Synapse.

Mycobacterium tuberculosis cell-wall glycolipids such as mannosylated lipoarabinomannan (ManLAM) can inhibit murine CD4+ T cells by blocking TCR signaling. This results in suppression of IL-2 production, reduced T cell proliferation, and induction of CD4+ T cell anergy. This study extended these findings to the interaction between primary human CD4+ T cells and macrophages infected by mycobacteria. Exposure of human CD4+ T cells to ManLAM before activation resulted in loss of polyfunctionality, as measured by IL-2, IFN-γ, and TNF-α expression, and reduced CD25 expression. This was not associated with upregulation of inhibitory receptors CTLA-4, PD-1, TIM-3, and Lag-3. By confocal microscopy and imaging flow cytometry, ManLAM exposure reduced conjugate formation between macrophages and CD4+ T cells. ManLAM colocalized to the immunological synapse (IS) and reduced translocation of lymphocyte-specific protein tyrosine kinase (LCK) to the IS. When CD4+ T cells and Mycobacterium bovis BCG-infected monocytes were cocultured, ManLAM colocalized to CD4+ T cells, which formed fewer conjugates with infected monocytes. These results demonstrate that mycobacterial cell-wall glycolipids such as ManLAM can traffic from infected macrophages to disrupt productive IS formation and inhibit CD4+ T cell activation, contributing to immune evasion by M. tuberculosis.

Long-range dependence and extreme values of precipitation, phosphorus load, and Cyanobacteria.

Extreme daily values of precipitation (1939-2021), discharge (1991-2021), phosphorus (P) load (1994-2021), and phycocyanin, a pigment of Cyanobacteria (June 1-September 15 of 2008-2021) are clustered as multi-day events for Lake Mendota, Wisconsin. Long-range dependence, or memory, is the shortest for precipitation and the longest for phycocyanin. Extremes are clustered for all variates and those of P load and phycocyanin are most strongly clustered. Extremes of P load are predictable from extremes of precipitation, and precipitation and P load are correlated with later concentrations of phycocyanin. However, time delays from 1 to 60 d were found between P load extremes and the next extreme phycocyanin event within the same year of observation. Although most of the lake's P enters in extreme events, blooms of Cyanobacteria may be sustained by recycling and food web processes.

A Call to Action: Urgently Strengthening the Future Physician-Scientist Workforce in Infectious Diseases.

Infectious diseases (ID) research is vital for global public health, typically led by physician-scientists. This Perspective addresses challenges in the ID workforce and suggests solutions. Physician-scientists have made key discoveries that have significantly impacted human health. The importance of ID research in understanding diseases, leading to treatments and vaccines, is emphasized, along with the need to address persistent and new infections, antimicrobial resistance, and threats like HIV and influenza. The paper analyzes the physician-scientist workforce's struggles, including funding, training, and research-practice integration gaps. We suggest increased funding, better training, and mentorship, more collaborative and interdisciplinary research, and improved recognition systems. The article stresses the urgency of supporting physician-scientists in ID, advocating for proactive prevention and preparedness, and calls for immediate action to enhance ID research and care.

Social dimensions of fertility behavior and consumption patterns in the Anthropocene.

We consider two aspects of the human enterprise that profoundly affect the global environment: population and consumption. We show that fertility and consumption behavior harbor a class of externalities that have not been much noted in the literature. Both are driven in part by attitudes and preferences that are not egoistic but socially embedded; that is, each household's decisions are influenced by the decisions made by others. In a famous paper, Garrett Hardin [G. Hardin, Science 162, 1243-1248 (1968)] drew attention to overpopulation and concluded that the solution lay in people "abandoning the freedom to breed." That human attitudes and practices are socially embedded suggests that it is possible for people to reduce their fertility rates and consumption demands without experiencing a loss in wellbeing. We focus on fertility in sub-Saharan Africa and consumption in the rich world and argue that bottom-up social mechanisms rather than top-down government interventions are better placed to bring about those ecologically desirable changes.

A natural polymorphism of Mycobacterium tuberculosis in the esxH gene disrupts immunodomination by the TB10.4-specific CD8 T cell response.

CD8 T cells provide limited protection against Mycobacterium tuberculosis (Mtb) infection in the mouse model. As Mtb causes chronic infection in mice and humans, we hypothesize that Mtb impairs T cell responses as an immune evasion strategy. TB10.4 is an immunodominant antigen in people, nonhuman primates, and mice, which is encoded by the esxH gene. In C57BL/6 mice, 30-50% of pulmonary CD8 T cells recognize the TB10.44-11 epitope. However, TB10.4-specific CD8 T cells fail to recognize Mtb-infected macrophages. We speculate that Mtb elicits immunodominant CD8 T cell responses to antigens that are inefficiently presented by infected cells, thereby focusing CD8 T cells on nonprotective antigens. Here, we leverage naturally occurring polymorphisms in esxH, which frequently occur in lineage 1 strains, to test this "decoy hypothesis". Using the clinical isolate 667, which contains an EsxHA10T polymorphism, we observe a drastic change in the hierarchy of CD8 T cells. Using isogenic Erd.EsxHA10T and Erd.EsxHWT strains, we prove that this polymorphism alters the hierarchy of immunodominant CD8 T cell responses. Our data are best explained by immunodomination, a mechanism by which competition for APC leads to dominant responses suppressing subdominant responses. These results were surprising as the variant epitope can bind to H2-Kb and is recognized by TB10.4-specific CD8 T cells. The dramatic change in TB10.4-specific CD8 responses resulted from increased proteolytic degradation of A10T variant, which destroyed the TB10.44-11epitope. Importantly, this polymorphism affected T cell priming and recognition of infected cells. These data support a model in which nonprotective CD8 T cells become immunodominant and suppress subdominant responses. Thus, polymorphisms between clinical Mtb strains, and BCG or H37Rv sequence-based vaccines could lead to a mismatch between T cells that are primed by vaccines and the epitopes presented by infected cells. Reprograming host immune responses should be considered in the future design of vaccines.

Production dynamics reveal hidden overharvest of inland recreational fisheries.

Recreational fisheries are valued at $190B globally and constitute the predominant way in which people use wild fish stocks in developed countries, with inland systems contributing the main fraction of recreational fisheries. Although inland recreational fisheries are thought to be highly resilient and self-regulating, the rapid pace of environmental change is increasing the vulnerability of these fisheries to overharvest and collapse. Here we directly evaluate angler harvest relative to the biomass production of individual stocks for a major inland recreational fishery. Using an extensive 28-y dataset of the walleye (Sander vitreus) fisheries in northern Wisconsin, United States, we compare empirical biomass harvest (Y) and calculated production (P) and biomass (B) for 390 lake year combinations. Production overharvest occurs when harvest exceeds production in that year. Biomass and biomass turnover (P/B) declined by ∼30 and ∼20%, respectively, over time, while biomass harvest did not change, causing overharvest to increase. Our analysis revealed that ∼40% of populations were production-overharvested, a rate >10× higher than estimates based on population thresholds often used by fisheries managers. Our study highlights the need to adapt harvest to changes in production due to environmental change.

Corridors of Clarity: Four Principles to Overcome Uncertainty Paralysis in the Anthropocene.

Global environmental change challenges humanity because of its broad scale, long-lasting, and potentially irreversible consequences. Key to an effective response is to use an appropriate scientific lens to peer through the mist of uncertainty that threatens timely and appropriate decisions surrounding these complex issues. Identifying such corridors of clarity could help understanding critical phenomena or causal pathways sufficiently well to justify taking policy action. To this end, we suggest four principles: Follow the strongest and most direct path between policy decisions on outcomes, focus on finding sufficient evidence for policy purpose, prioritize no-regrets policies by avoiding options with controversial, uncertain, or immeasurable benefits, aim for getting the big picture roughly right rather than focusing on details.

Reversal of a cyanobacterial bloom in response to early warnings.

Directional change in environmental drivers sometimes triggers regime shifts in ecosystems. Theory and experiments suggest that regime shifts can be detected in advance, and perhaps averted, by monitoring resilience indicators such as variance and autocorrelation of key ecosystem variables. However, it is uncertain whether management action prompted by a change in resilience indicators can prevent an impending regime shift. We caused a cyanobacterial bloom by gradually enriching an experimental lake while monitoring an unenriched reference lake and a continuously enriched reference lake. When resilience indicators exceeded preset boundaries, nutrient enrichment was stopped in the experimental lake. Concentrations of algal pigments, dissolved oxygen saturation, and pH rapidly declined following cessation of nutrient enrichment and became similar to the unenriched lake, whereas a large bloom occurred in the continuously enriched lake. This outcome suggests that resilience indicators may be useful in management to prevent unwanted regime shifts, at least in some situations. Nonetheless, a safer approach to ecosystem management would build and maintain the resilience of desirable ecosystem conditions, for example, by preventing excessive nutrient input to lakes and reservoirs.

Vaccine-elicited memory CD4+ T cell expansion is impaired in the lungs during tuberculosis.

Immunological memory is the key biological process that makes vaccines possible. Although tuberculosis vaccines elicit protective immunity in animals, few provide durable protection. To understand why protection is transient, we evaluated the ability of memory CD4+ T cells to expand, differentiate, and control Mycobacterium tuberculosis. Both naïve and memory CD4+ T cells initially proliferated exponentially, and the accumulation of memory T cells in the lung correlated with early bacterial control. However, later during infection, memory CD4+ T cell proliferation was curtailed and no protection was observed. We show that memory CD4+ T cells are first activated in the LN and their recruitment to the lung attenuates bacterial growth. However, their interaction with Mtb-infected macrophages does not promote continued proliferation. We conclude that a lack of sustained expansion by memory-derived T cells in the lung limits the durability of their protection, linking their slower expansion with transient protection in vaccinated mice.

Invasive species triggers a massive loss of ecosystem services through a trophic cascade.

Despite growing recognition of the importance of ecosystem services and the economic and ecological harm caused by invasive species, linkages between invasions, changes in ecosystem functioning, and in turn, provisioning of ecosystem services remain poorly documented and poorly understood. We evaluate the economic impacts of an invasion that cascaded through a food web to cause substantial declines in water clarity, a valued ecosystem service. The predatory zooplankton, the spiny water flea (Bythotrephes longimanus), invaded the Laurentian Great Lakes in the 1980s and has subsequently undergone secondary spread to inland lakes, including Lake Mendota (Wisconsin), in 2009. In Lake Mendota, Bythotrephes has reached unparalleled densities compared with in other lakes, decreasing biomass of the grazer Daphnia pulicaria and causing a decline in water clarity of nearly 1 m. Time series modeling revealed that the loss in water clarity, valued at US$140 million (US$640 per household), could be reversed by a 71% reduction in phosphorus loading. A phosphorus reduction of this magnitude is estimated to cost between US$86.5 million and US$163 million (US$430-US$810 per household). Estimates of the economic effects of Great Lakes invasive species may increase considerably if cases of secondary invasions into inland lakes, such as Lake Mendota, are included. Furthermore, such extreme cases of economic damages call for increased investment in the prevention and control of invasive species to better maximize the economic benefits of such programs. Our results highlight the need to more fully incorporate ecosystem services into our analysis of invasive species impacts, management, and public policy.

A Higher Activation Threshold of Memory CD8+ T Cells Has a Fitness Cost That Is Modified by TCR Affinity during Tuberculosis.

T cell vaccines against Mycobacterium tuberculosis (Mtb) and other pathogens are based on the principle that memory T cells rapidly generate effector responses upon challenge, leading to pathogen clearance. Despite eliciting a robust memory CD8+ T cell response to the immunodominant Mtb antigen TB10.4 (EsxH), we find the increased frequency of TB10.4-specific CD8+ T cells conferred by vaccination to be short-lived after Mtb challenge. To compare memory and naïve CD8+ T cell function during their response to Mtb, we track their expansions using TB10.4-specific retrogenic CD8+ T cells. We find that the primary (naïve) response outnumbers the secondary (memory) response during Mtb challenge, an effect moderated by increased TCR affinity. To determine whether the expansion of polyclonal memory T cells is restrained following Mtb challenge, we used TCRß deep sequencing to track TB10.4-specific CD8+ T cells after vaccination and subsequent challenge in intact mice. Successful memory T cells, defined by their clonal expansion after Mtb challenge, express similar CDR3ß sequences suggesting TCR selection by antigen. Thus, both TCR-dependent and -independent factors affect the fitness of memory CD8+ responses. The impaired expansion of the majority of memory T cell clonotypes may explain why some TB vaccines have not provided better protection.

Scenarios reveal pathways to sustain future ecosystem services in an agricultural landscape.

Sustaining food production, water quality, soil retention, flood, and climate regulation in agricultural landscapes is a pressing global challenge given accelerating environmental changes. Scenarios are stories about plausible futures, and scenarios can be integrated with biophysical simulation models to explore quantitatively how the future might unfold. However, few studies have incorporated a wide range of drivers (e.g., climate, land-use, management, population, human diet) in spatially explicit, process-based models to investigate spatial-temporal dynamics and relationships of a portfolio of ecosystem services. Here, we simulated nine ecosystem services (three provisioning and six regulating services) at 220 × 220 m from 2010 to 2070 under four contrasting scenarios in the 1,345-km2 Yahara Watershed (Wisconsin, USA) using Agro-IBIS, a dynamic model of terrestrial ecosystem processes, biogeochemistry, water, and energy balance. We asked (1) How does ecosystem service supply vary among alternative future scenarios? (2) Where on the landscape is the provision of ecosystem services most susceptible to future social-ecological changes? (3) Among alternative future scenarios, are relationships (i.e., trade-offs, synergies) among food production, water, and biogeochemical services consistent over time? Our results showed that food production varied substantially with future land-use choices and management, and its trade-offs with water quality and soil retention persisted under most scenarios. However, pathways to mitigate or even reverse such trade-offs through technological advances and sustainable agricultural practices were apparent. Consistent relationships among regulating services were identified across scenarios (e.g., trade-offs of freshwater supply vs. flood and climate regulation, and synergies among water quality, soil retention, and climate regulation), suggesting opportunities and challenges to sustaining these services. In particular, proactive land-use changes and management may buffer water quality against undesirable future climate changes, but changing climate may overwhelm management efforts to sustain freshwater supply and flood regulation. Spatially, changes in ecosystem services were heterogeneous across the landscape, underscoring the power of local actions and fine-scale management. Our research highlights the value of embracing spatial and temporal perspectives in managing ecosystem services and their complex interactions, and provides a system-level understanding for achieving sustainability of the food-water-climate nexus in agricultural landscapes.

Multiple Inflammatory Cytokines Converge To Regulate CD8+ T Cell Expansion and Function during Tuberculosis.

The differentiation of effector CD8(+) T cells is a dynamically regulated process that varies during different infections and is influenced by the inflammatory milieu of the host. In this study, we define three signals regulating CD8(+) T cell responses during tuberculosis by focusing on cytokines known to affect disease outcome: IL-12, type I IFN, and IL-27. Using mixed bone marrow chimeras, we compared wild-type and cytokine receptor knockout CD8(+) T cells within the same mouse following aerosol infection with Mycobacterium tuberculosis. Four weeks postinfection, IL-12, type 1 IFN, and IL-27 were all required for efficient CD8(+) T cell expansion in the lungs. We next determined if these cytokines directly promote CD8(+) T cell priming or are required only for expansion in the lungs. Using retrogenic CD8(+) T cells specific for the M. tuberculosis Ag TB10.4 (EsxH), we observed that IL-12 is the dominant cytokine driving both CD8(+) T cell priming in the lymph node and expansion in the lungs; however, type I IFN and IL-27 have nonredundant roles supporting pulmonary CD8(+) T cell expansion. Thus, IL-12 is a major signal promoting priming in the lymph node, but a multitude of inflammatory signals converge in the lung to promote continued expansion. Furthermore, these cytokines regulate the differentiation and function of CD8(+) T cells during tuberculosis. These data demonstrate distinct and overlapping roles for each of the cytokines examined and underscore the complexity of CD8(+) T cell regulation during tuberculosis.

Orchestration of pulmonary T cell immunity during Mycobacterium tuberculosis infection: immunity interruptus.

Despite the introduction almost a century ago of Mycobacterium bovis BCG (BCG), an attenuated form of M. bovis that is used as a vaccine against Mycobacterium tuberculosis, tuberculosis remains a global health threat and kills more than 1.5 million people each year. This is mostly because BCG fails to prevent pulmonary disease--the contagious form of tuberculosis. Although there have been significant advances in understanding how the immune system responds to infection, the qualities that define protective immunity against M. tuberculosis remain poorly characterized. The ability to predict who will maintain control over the infection and who will succumb to clinical disease would revolutionize our approach to surveillance, control, and treatment. Here we review the current understanding of pulmonary T cell responses following M. tuberculosis infection. While infection elicits a strong immune response that contains infection, M. tuberculosis evades eradication. Traditionally, its intracellular lifestyle and alteration of macrophage function are viewed as the dominant mechanisms of evasion. Now we appreciate that chronic inflammation leads to T cell dysfunction. While this may arise as the host balances the goals of bacterial sterilization and avoidance of tissue damage, it is becoming clear that T cell dysfunction impairs host resistance. Defining the mechanisms that lead to T cell dysfunction is crucial as memory T cell responses are likely to be subject to the same subject to the same pressures. Thus, success of T cell based vaccines is predicated on memory T cells avoiding exhaustion while at the same time not promoting overt tissue damage.

Allowing variance may enlarge the safe operating space for exploited ecosystems.

Variable flows of food, water, or other ecosystem services complicate planning. Management strategies that decrease variability and increase predictability may therefore be preferred. However, actions to decrease variance over short timescales (2-4 y), when applied continuously, may lead to long-term ecosystem changes with adverse consequences. We investigated the effects of managing short-term variance in three well-understood models of ecosystem services: lake eutrophication, harvest of a wild population, and yield of domestic herbivores on a rangeland. In all cases, actions to decrease variance can increase the risk of crossing critical ecosystem thresholds, resulting in less desirable ecosystem states. Managing to decrease short-term variance creates ecosystem fragility by changing the boundaries of safe operating spaces, suppressing information needed for adaptive management, cancelling signals of declining resilience, and removing pressures that may build tolerance of stress. Thus, the management of variance interacts strongly and inseparably with the management of resilience. By allowing for variation, learning, and flexibility while observing change, managers can detect opportunities and problems as they develop while sustaining the capacity to deal with them.

Human and Murine Clonal CD8+ T Cell Expansions Arise during Tuberculosis Because of TCR Selection.

The immune system can recognize virtually any antigen, yet T cell responses against several pathogens, including Mycobacterium tuberculosis, are restricted to a limited number of immunodominant epitopes. The host factors that affect immunodominance are incompletely understood. Whether immunodominant epitopes elicit protective CD8+ T cell responses or instead act as decoys to subvert immunity and allow pathogens to establish chronic infection is unknown. Here we show that anatomically distinct human granulomas contain clonally expanded CD8+ T cells with overlapping T cell receptor (TCR) repertoires. Similarly, the murine CD8+ T cell response against M. tuberculosis is dominated by TB10.44-11-specific T cells with extreme TCRß bias. Using a retro genic model of TB10.44-11-specific CD8+ Tcells, we show that TCR dominance can arise because of competition between clonotypes driven by differences in affinity. Finally, we demonstrate that TB10.4-specific CD8+ T cells mediate protection against tuberculosis, which requires interferon-γ production and TAP1-dependent antigen presentation in vivo. Our study of how immunodominance, biased TCR repertoires, and protection are inter-related, provides a new way to measure the quality of T cell immunity, which if applied to vaccine evaluation, could enhance our understanding of how to elicit protective T cell immunity.

The consistency of a species' response to press perturbations with high food web uncertainty.

Predicting species responses to perturbations is a fundamental challenge in ecology. Decision makers must often identify management perturbations that are the most likely to deliver a desirable management outcome despite incomplete information on the pattern and strength of food web links. Motivated by a current fishery decline in inland lakes of the Midwestern United States, we evaluate consistency of the responses of a target species (walleye [Sander vitreus]) to press perturbations. We represented food web uncertainty with 193 plausible topological models and applied four perturbations to each one. Frequently the direction of the focal predator response to the same perturbation is not consistent across food web topologies. Simultaneous application of management perturbations led to less consistent outcomes compared to the best single perturbation. However, direct manipulation of the adult focal predator produced a desirable outcome in 77% of 193 plausible topologies. Identifying perturbations that produce consistent outcomes in the face of food web uncertainty can have important implications for natural resource conservation and management efforts.

Solutions for a cultivated planet.

Increasing population and consumption are placing unprecedented demands on agriculture and natural resources. Today, approximately a billion people are chronically malnourished while our agricultural systems are concurrently degrading land, water, biodiversity and climate on a global scale. To meet the world's future food security and sustainability needs, food production must grow substantially while, at the same time, agriculture's environmental footprint must shrink dramatically. Here we analyse solutions to this dilemma, showing that tremendous progress could be made by halting agricultural expansion, closing 'yield gaps' on underperforming lands, increasing cropping efficiency, shifting diets and reducing waste. Together, these strategies could double food production while greatly reducing the environmental impacts of agriculture.