Structure of HLA-A*0301 in complex with a peptide of proteolipid protein: insights into the role of HLA-A alleles in susceptibility to multiple sclerosis

The structure of the human major histocompatability (MHC) class I molecule HLA-A*0301 (HLA-A3) in complex with a nonameric peptide (KLIETYFSK) has been determined by X-ray crystallography to 2.7 Å resolution. HLA-A3 is a predisposing allele for multiple sclerosis (MS), an autoimmune disease of the central nervous system. The KLIETYFSK peptide is a naturally processed epitope of proteolipid protein, a myelin protein and candidate target for immune-mediated myelin destruction in MS. Comparison of the structure of HLA-A3 with that of HLA-A2, an MHC class I molecule which is protective against MS, indicates that both MHC class I molecules present very similar faces for T-cell receptor recognition whilst differing in the specificity of their peptide-binding grooves. These characteristics may underlie the opposing (predisposing versus protective) associations that they exhibit both in humans and in mouse models of MS-like disease. Furthermore, subtle alterations within the peptide-binding groove of HLA-A3 and other A3-like MHC class I molecules, members of the so-called A3 superfamily, may be sufficient to alter their presentation of autoantigen peptides such as KLIETYFSK. This in turn may modulate their contribution to the associated risk of autoimmune disease

Supraglacial debris thickness and supply rate in High-Mountain Asia

Supraglacial debris strongly modulates glacier melt rates and can be decisive for ice dynamics and mountain hydrology. It is ubiquitous in High-Mountain Asia, yet because its thickness and supply rate from local topography are poorly known, our ability to forecast regional glacier change and streamflow is limited. Here we combined remote sensing and numerical modelling to resolve supraglacial debris thickness by altitude for 4689 glaciers in High-Mountain Asia, and debris-supply rate to 4141 of those glaciers. Our results reveal extensively thin supraglacial debris and high spatial variability in both debris thickness and supply rate. Debris-supply rate increases with the temperature and slope of debris-supply slopes regionally, and debris thickness increases as ice flow decreases locally. Our centennial-scale estimates of debris-supply rate are typically an order of magnitude or more lower than millennial-scale estimates of headwall-erosion rate from Beryllium-10 cosmogenic nuclides, potentially reflecting episodic debris supply to the region’s glaciers

Interannual Dynamics of Ice Cliff Populations on Debris‐Covered Glaciers from Remote Sensing Observations and Stochastic Modeling

Ice cliffs are common on debris-covered glaciers and have relatively high melt rates due to their direct exposure to incoming radiation. Previous studies have shown that their number and relative area can change considerably from year to year, but this variability has not been explored, in part because available cliff observations are irregular. Here, we systematically mapped and tracked ice cliffs across four debris-covered glaciers in High Mountain Asia for every late ablation season from 2009 to 2019 using high-resolution multi-spectral satellite imagery. We then quantified the processes occurring at the feature scale to train a stochastic birth-death model to represent the cliff population dynamics. Our results show that while the cliff relative area can change by up to 20% from year to year, the natural long-term variability is constrained, thus defining a glacier-specific cliff carrying capacity. In a subsequent step, the inclusion of external drivers related to climate, glacier dynamics and hydrology highlights the influence of these variables on the cliff population dynamics, which is usually not a direct one due to the complexity and interdependence of the processes taking place at the glacier surface. In some extreme cases (here, a glacier surge), these external drivers may lead to a reorganization of the cliffs at the glacier surface and a change in the natural variability. These results have implications for the melt of debris-covered glaciers, in addition to showing the high rate of changes at their surface and highlighting some of the links between cliff population and glacier state

Warming-induced monsoon precipitation phase change intensifies glacier mass loss in the southeastern Tibetan Plateau

Glaciers are key components of the mountain water towers of Asia and are vital for downstream domestic, agricultural, and industrial uses. The glacier mass loss rate over the southeastern Tibetan Plateau is among the highest in Asia and has accelerated in recent decades. This acceleration has been attributed to increased warming, but the mechanisms behind these glaciers’ high sensitivity to warming remain unclear, while the influence of changes in precipitation over the past decades is poorly quantified. Here, we reconstruct glacier mass changes and catchment runoff since 1975 at a benchmark glacier, Parlung No. 4, to shed light on the drivers of recent mass losses for the monsoonal, spring-accumulation glaciers of the Tibetan Plateau. Our modeling demonstrates how a temperature increase (mean of 0.39 ∘ C ⋅dec −1 since 1990) has accelerated mass loss rates by altering both the ablation and accumulation regimes in a complex manner. The majority of the post-2000 mass loss occurred during the monsoon months, caused by simultaneous decreases in the solid precipitation ratio (from 0.70 to 0.56) and precipitation amount (–10%), leading to reduced monsoon accumulation (–26%). Higher solid precipitation in spring (+18%) during the last two decades was increasingly important in mitigating glacier mass loss by providing mass to the glacier and protecting it from melting in the early monsoon. With bare ice exposed to warmer temperatures for longer periods, icemelt and catchment discharge have unsustainably intensified since the start of the 21st century, raising concerns for long-term water supply and hazard occurrence in the region

P16-23. Antigen processing influences HIV-specific cytotoxic T lymphocyte immunodominance

International audienc

Multi-decadal monsoon characteristics and glacier response in High Mountain Asia

Glacier health across High Mountain Asia (HMA) is highly heterogeneous and strongly governed by regional climate, which is variably influenced by monsoon dynamics and the westerlies. We explore four decades of glacier energy and mass balance at three climatically distinct sites across HMA by utilising a detailed land surface model driven by bias-corrected Weather Research and Forecasting meteorological forcing. All three glaciers have experienced long-term mass losses (ranging from −0.04 ± 0.09 to −0.59 ± 0.20 m w.e. a−1) consistent with widespread warming across the region. However, complex and contrasting responses of glacier energy and mass balance to the patterns of the Indian Summer Monsoon were evident, largely driven by the role snowfall timing, amount and phase. A later monsoon onset generates less total snowfall to the glacier in the southeastern Tibetan Plateau during May–June, augmenting net shortwave radiation and affecting annual mass balance (−0.5 m w.e. on average compared to early onset years). Conversely, timing of the monsoon’s arrival has limited impact for the Nepalese Himalaya which is more strongly governed by the temperature and snowfall amount during the core monsoon season. In the arid central Tibetan Plateau, a later monsoon arrival results in a 40 mm (58%) increase of May–June snowfall on average compared to early onset years, likely driven by the greater interaction of westerly storm events. Meanwhile, a late monsoon cessation at this site sees an average 200 mm (192%) increase in late summer precipitation due to monsoonal storms. A trend towards weaker intensity monsoon conditions in recent decades, combined with long-term warming patterns, has produced predominantly negative glacier mass balances for all sites (up to 1 m w.e. more mass loss in the Nepalese Himalaya compared to strong monsoon intensity years) but sub-regional variability in monsoon timing can additionally complicate this response

Understanding monsoon controls on the energy and mass balance of glaciers in the Central and Eastern Himalaya

The Indian and East Asian summer monsoons shape the melt and accumulation patterns of glaciers in High Mountain Asia in complex ways due to the interaction of persistent cloud cover, large temperature ranges, high atmospheric water content and high precipitation rates. Glacier energy- and mass-balance modelling using in situ measurements offers insights into the ways in which surface processes are shaped by climatic regimes. In this study, we use a full energy- and mass-balance model and seven on-glacier automatic weather station datasets from different parts of the Central and Eastern Himalaya to investigate how monsoon conditions influence the glacier surface energy and mass balance. In particular, we look at how debris-covered and debris-free glaciers respond differently to monsoonal conditions. The radiation budget primarily controls the melt of clean-ice glaciers, but turbulent fluxes play an important role in modulating the melt energy on debris-covered glaciers. The sensible heat flux decreases during core monsoon, but the latent heat flux cools the surface due to evaporation of liquid water. This interplay of radiative and turbulent fluxes causes debris-covered glacier melt rates to stay almost constant through the different phases of the monsoon. Ice melt under thin debris, on the other hand, is amplified by both the dark surface and the turbulent fluxes, which intensify melt during monsoon through surface heating and condensation. Pre-monsoon snow cover can considerably delay melt onset and have a strong impact on the seasonal mass balance. Intermittent monsoon snow cover lowers the melt rates at high elevation. This work is fundamental to the understanding of the present and future Himalayan cryosphere and water budget, while informing and motivating further glacier- and catchment-scale research using process-based models

A Comparative Approach Linking Molecular Dynamics of Altered Peptide Ligands and MHC with In Vivo Immune Responses

The recognition of peptide in the context of MHC by T lymphocytes is a critical step in the initiation of an adaptive immune response. However, the molecular nature of the interaction between peptide and MHC and how it influences T cell responsiveness is not fully understood.We analyzed the immunological consequences of the interaction of MHC class II (I-Au) restricted 11-mer peptides of myelin basic protein with amino acid substitutions at position 4. These mutant peptides differ in MHC binding affinity, CD4+ T cell priming, and alter the severity of peptide-induced experimental allergic encephalomyelitis. Using molecular dynamics, a computational method of quantifying intrinsic movements of proteins at high resolution, we investigated conformational changes in MHC upon peptide binding. We found that irrespective of peptide binding affinity, MHC deformation appears to influence costimulation, which then leads to effective T cell priming and disease induction. Although this study compares in vivo and molecular dynamics results for three altered peptide ligands, further investigation with similar complexes is essential to determine whether spatial rearrangement of peptide-MHC and costimulatory complexes is an additional level of T cell regulation