Worldwide, each year over 30,000 patients undergo an allogeneic hema-topoietic stem cell transplantation with the intent to cure high-risk hematologic malignancy, immunodeficiency, metabolic disease, ...or a life-threatening bone marrow failure syndrome. Despite substantial advances in donor selection and conditioning regimens and greater availability of allograft sources, transplant recipients still endure the morbidity and mortality of graft-versus-host disease (GVHD). Herein, we identify key aspects of acute and chronic GVHD pathophysiology, including host donor cell effectors, gut dysbiosis, immune system and cytokine imbalance, and the interface between inflammation and tissue fibrosis. In particular, we also summarize the translational application of this heightened understanding of immune dysregulation in the design of novel therapies to prevent and treat GVHD.
CD8(+) T cell exhaustion represents a major hallmark of chronic HIV infection. Two key transcription factors governing CD8(+) T cell differentiation, T-bet and Eomesodermin (Eomes), have previously ...been shown in mice to differentially regulate T cell exhaustion in part through direct modulation of PD-1. Here, we examined the relationship between these transcription factors and the expression of several inhibitory receptors (PD-1, CD160, and 2B4), functional characteristics and memory differentiation of CD8(+) T cells in chronic and treated HIV infection. The expression of PD-1, CD160, and 2B4 on total CD8(+) T cells was elevated in chronically infected individuals and highly associated with a T-bet(dim)Eomes(hi) expressional profile. Interestingly, both resting and activated HIV-specific CD8(+) T cells in chronic infection were almost exclusively T-bet(dim)Eomes(hi) cells, while CMV-specific CD8(+) T cells displayed a balanced expression pattern of T-bet and Eomes. The T-bet(dim)Eomes(hi) virus-specific CD8(+) T cells did not show features of terminal differentiation, but rather a transitional memory phenotype with poor polyfunctional (effector) characteristics. The transitional and exhausted phenotype of HIV-specific CD8(+) T cells was longitudinally related to persistent Eomes expression after antiretroviral therapy (ART) initiation. Strikingly, these characteristics remained stable up to 10 years after ART initiation. This study supports the concept that poor human viral-specific CD8(+) T cell functionality is due to an inverse expression balance between T-bet and Eomes, which is not reversed despite long-term viral control through ART. These results aid to explain the inability of HIV-specific CD8(+) T cells to control the viral replication post-ART cessation.
Continental runoff has increased through the twentieth century despite more intensive human water consumption. Possible reasons for the increase include: climate change and variability, ...deforestation, solar dimming, and direct atmospheric carbon dioxide (CO2) effects on plant transpiration. All of these mechanisms have the potential to affect precipitation and/or evaporation and thereby modify runoff. Here we use a mechanistic land-surface model and optimal fingerprinting statistical techniques to attribute observational runoff changes into contributions due to these factors. The model successfully captures the climate-driven inter-annual runoff variability, but twentieth-century climate alone is insufficient to explain the runoff trends. Instead we find that the trends are consistent with a suppression of plant transpiration due to CO2-induced stomatal closure. This result will affect projections of freshwater availability, and also represents the detection of a direct CO2 effect on the functioning of the terrestrial biosphere.
Higher evaporative demands and more frequent and persistent dry spells associated with rising temperatures suggest that drought conditions could worsen in many regions of the world. In this study, we ...assess how drought conditions may develop across the globe for 1.5, 2, and 3°C warming compared to preindustrial temperatures. Results show that two thirds of global population will experience a progressive increase in drought conditions with warming. For drying areas, drought durations are projected to rise at rapidly increasing rates with warming, averaged globally from 2.0 month/°C below 1.5°C to 4.2 month/°C when approaching 3°C. Drought magnitudes could double for 30% of global landmass under stringent mitigation. If contemporary warming rates continue, water supply‐demand deficits could become fivefold in size for most of Africa, Australia, southern Europe, southern and central states of the United States, Central America, the Caribbean, north‐west China, and parts of Southern America. In approximately 20% of the global land surface, drought magnitude will halve with warming of 1.5°C and higher levels, mainly most land areas north of latitude 55°N, but also parts of South America and Eastern and South‐eastern Asia. A progressive and significant increase in frequency of droughts is projected with warming in the Mediterranean basin, most of Africa, West and Southern Asia, Central America, and Oceania, where droughts are projected to happen 5 to 10 times more frequent even under ambitious mitigation targets and current 100‐year events could occur every two to five years under 3°C of warming.
Plain Language Summary
This research investigates the climatology of global drought conditions under different global warming levels. We consider warming levels of 1.5 and 2°C set out as mitigation targets in the Paris Agreement, as well as 3°C that is closer to what is expected by the end of the 21st century if current emission trends are retained. We found that the magnitude of droughts is likely to double in 30% of the global landmass under stringent mitigation policies. If global warming continues at the present rate, water supply‐demand deficits would increase fivefold while current 1‐in‐100‐year droughts would occur every two to five years for most of Africa, Australia, southern Europe, southern and central United States, Central America, the Caribbean, north‐west China, and parts of Southern America. Approximately two thirds of the global population will experience a progressive increase in drought hazard with warming. In drying areas, drought durations are projected to rise rapidly with warming. The main impacts of long‐lasting droughts are linked to the lowering of the groundwater and of the water levels in reservoirs. This will impede replenishment of water supplies and may result in a difficult recovery and prolonged socio‐economic impacts after severe droughts.
Key Points
This paper proposes a methodology for assessing global changes in drought characteristics under different warming levels, including an assessment of the related uncertainties
Drought magnitude will halve in 20% of the global land surface with warming of 1.5°C and higher levels
A progressive and significant increase in frequency of droughts is projected with warming in the Mediterranean basin, most of Africa, West and Southern Asia, Central America, and Oceania, where droughts are projected to happen 5 to 10 times more frequent even under ambitious mitigation targets
SARS-CoV-2 messenger RNA vaccination in healthy individuals generates immune protection against COVID-19. However, little is known about SARS-CoV-2 mRNA vaccine-induced responses in immunosuppressed ...patients. We investigated induction of antigen-specific antibody, B cell and T cell responses longitudinally in patients with multiple sclerosis (MS) on anti-CD20 antibody monotherapy (n = 20) compared with healthy controls (n = 10) after BNT162b2 or mRNA-1273 mRNA vaccination. Treatment with anti-CD20 monoclonal antibody (aCD20) significantly reduced spike-specific and receptor-binding domain (RBD)-specific antibody and memory B cell responses in most patients, an effect ameliorated with longer duration from last aCD20 treatment and extent of B cell reconstitution. By contrast, all patients with MS treated with aCD20 generated antigen-specific CD4 and CD8 T cell responses after vaccination. Treatment with aCD20 skewed responses, compromising circulating follicular helper T (T
) cell responses and augmenting CD8 T cell induction, while preserving type 1 helper T (T
1) cell priming. Patients with MS treated with aCD20 lacking anti-RBD IgG had the most severe defect in circulating T
responses and more robust CD8 T cell responses. These data define the nature of the SARS-CoV-2 vaccine-induced immune landscape in aCD20-treated patients and provide insights into coordinated mRNA vaccine-induced immune responses in humans. Our findings have implications for clinical decision-making and public health policy for immunosuppressed patients including those treated with aCD20.
In preparation for the fifth Assessment Report (AR5) of the Intergovernmental Panel on Climate Change (IPCC), the international community is developing new advanced Earth System Models (ESMs) to ...assess the combined effects of human activities (e.g. land use and fossil fuel emissions) on the carbon-climate system. In addition, four Representative Concentration Pathway (RCP) scenarios of the future (2005–2100) are being provided by four Integrated Assessment Model (IAM) teams to be used as input to the ESMs for future carbon-climate projections (Moss et al.
2010
). The diversity of approaches and requirements among IAMs and ESMs for tracking land-use change, along with the dependence of model projections on land-use history, presents a challenge for effectively passing data between these communities and for smoothly transitioning from the historical estimates to future projections. Here, a harmonized set of land-use scenarios are presented that smoothly connects historical reconstructions of land use with future projections, in the format required by ESMs. The land-use harmonization strategy estimates fractional land-use patterns and underlying land-use transitions annually for the time period 1500–2100 at 0.5° × 0.5° resolution. Inputs include new gridded historical maps of crop and pasture data from HYDE 3.1 for 1500–2005, updated estimates of historical national wood harvest and of shifting cultivation, and future information on crop, pasture, and wood harvest from the IAM implementations of the RCPs for the period 2005–2100. The computational method integrates these multiple data sources, while minimizing differences at the transition between the historical reconstruction ending conditions and IAM initial conditions, and working to preserve the future changes depicted by the IAMs at the grid cell level. This study for the first time harmonizes land-use history data together with future scenario information from multiple IAMs into a single consistent, spatially gridded, set of land-use change scenarios for studies of human impacts on the past, present, and future Earth system.
Carbon uptake by forestation is one method proposed to reduce
net carbon dioxide emissions to the atmosphere and so limit the radiative
forcing of climate change. But the overall impact of ...forestation
on climate will also depend on other effects associated with the creation
of new forests. In particular, the albedo of a forested landscape is generally
lower than that of cultivated land, especially when snow is lying,
and decreasing albedo exerts a positive radiative forcing on climate. Here
I simulate the radiative forcings associated with changes in surface albedo
as a result of forestation in temperate and boreal forest areas, and translate
these forcings into equivalent changes in local carbon stock for comparison
with estimated carbon sequestration potentials. I
suggest that in many boreal forest areas, the positive forcing induced by
decreases in albedo can offset the negative forcing that is expected from
carbon sequestration. Some high-latitude forestation activities may therefore
increase climate change, rather than mitigating it as intended.
SARS-CoV-2 mRNA vaccines have shown remarkable clinical efficacy, but questions remain about the nature and kinetics of T cell priming. We performed longitudinal antigen-specific T cell analyses on ...healthy SARS-CoV-2-naive and recovered individuals prior to and following mRNA prime and boost vaccination. Vaccination induced rapid antigen-specific CD4+ T cell responses in naive subjects after the first dose, whereas CD8+ T cell responses developed gradually and were variable in magnitude. Vaccine-induced Th1 and Tfh cell responses following the first dose correlated with post-boost CD8+ T cells and neutralizing antibodies, respectively. Integrated analysis revealed coordinated immune responses with distinct trajectories in SARS-CoV-2-naive and recovered individuals. Last, whereas booster vaccination improved T cell responses in SARS-CoV-2-naive subjects, the second dose had little effect in SARS-CoV-2-recovered individuals. These findings highlight the role of rapidly primed CD4+ T cells in coordinating responses to the second vaccine dose in SARS-CoV-2-naive individuals.
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•mRNA vaccines generate antigen-specific T cells in a coordinated immune response•Vaccine-induced T cells resemble the durable memory cells primed by infection•Th1 and cTfh cell responses to the first dose correlate with second-dose responses•SARS-CoV-2-recovered individuals benefit from the first but not the second dose
SARS-CoV-2 mRNA vaccines have demonstrated remarkable efficacy, but T cell responses to vaccination have not been well studied. In a longitudinal cohort, Painter et al. show that mRNA vaccines activate SARS-CoV-2-specific T cells that could contribute to durable immunity. The findings highlight the central role of T cells in the two-dose vaccine regimen for individuals not previously infected with SARS-CoV-2.
Coronavirus disease 2019 (COVID-19) is currently a global pandemic, but human immune responses to the virus remain poorly understood. We used high-dimensional cytometry to analyze 125 COVID-19 ...patients and compare them with recovered and healthy individuals. Integrated analysis of ~200 immune and ~50 clinical features revealed activation of T cell and B cell subsets in a proportion of patients. A subgroup of patients had T cell activation characteristic of acute viral infection and plasmablast responses reaching >30% of circulating B cells. However, another subgroup had lymphocyte activation comparable with that in uninfected individuals. Stable versus dynamic immunological signatures were identified and linked to trajectories of disease severity change. Our analyses identified three immunotypes associated with poor clinical trajectories versus improving health. These immunotypes may have implications for the design of therapeutics and vaccines for COVID-19.
Mucosa-associated invariant T (MAIT) cells are unconventional innate-like T cells that recognize microbial riboflavin metabolites presented by the MHC class I-like protein MR1. Human MAIT cells ...predominantly express the CD8α coreceptor (CD8⁺), with a smaller subset lacking both CD4 and CD8 (double-negative, DN). However, it is unclear if these two MAIT cell subpopulations distinguished by CD8α represent functionally distinct subsets. Here, we show that the two MAIT cell subsets express divergent transcriptional programs and distinct patterns of classic T cell transcription factors. Furthermore, CD8⁺ MAIT cells have higher levels of receptors for IL-12 and IL-18, as well as of the activating receptors CD2, CD9, and NKG2D, and display superior functionality following stimulation with riboflavin-autotrophic as well as riboflavin-auxotrophic bacterial strains. DN MAIT cells display higher RORγt/T-bet ratio, and express less IFN-γ and more IL-17. Furthermore, the DN subset displays enrichment of an apoptosis gene signature and higher propensity for activation-induced apoptosis. During development in human fetal tissues, DN MAIT cells are more mature and accumulate over gestational time with reciprocal contraction of the CD8⁺ subset. Analysis of the T cell receptor repertoire reveals higher diversity in CD8⁺ MAIT cells than in DN MAIT cells. Finally, chronic T cell receptor stimulation of CD8⁺ MAIT cells in an in vitro culture system supports the accumulation and maintenance of the DN subpopulation. These findings define human CD8⁺ and DN MAIT cells as functionally distinct subsets and indicate a derivative developmental relationship.
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