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At least 73 records · Page 4

All sources NASA NTRS DOE OSTI

DOE OSTI2018

CD1d is a novel cell-surface marker for human monocytic myeloid-derived suppressor cells with T cell suppression activity in peripheral blood after allogeneic hematopoietic stem cell transplantation

Highlights: • High-content screening identified a set of cell-surface marker candidates expressed in HLA-DR{sup -}CD14{sup +} M-MDSCs. • CD1d and CD226 are novel markers for the human M-MDSC subset. • CD1d-expressing M-MDSC showed the suppressive activity of T cell proliferation and could be a valuable marker for of human M-MDSCs. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of cells that regulate immune responses in cancer and various pathological conditions. However, the phenotypic and functional heterogeneity of human MDSCs represents a major hurdle for the development of therapeutic strategies targeting or regulating MDSCs in tumor progression, inflammation, and graft-versus-host disease (GVHD). We previously shown that circulating HLA-DR{sup -}CD14{sup +} monocytic MDSCs are a major contributor to clinical outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). In this study, we identified, using high-throughput screening, a set of surface markers that are strongly expressed in HLA-DR{sup -}CD14{sup +} monocytic MDSCs isolated from the peripheral blood (PB) of patients receiving allo-HSCT. Subsequent experiments showed the consistent dominant expression of CD1d in monocytic MDSCs of allo-HSCT PB in comparison with granulocytic MDSCs. In addition, CD1d-expressing cells isolated from PB of allo-HSCT patients showed the suppressive activity of T cell proliferation and higher expression of MyD88 and IDO compared with CD1d{sup −} cells. Our results suggest that CD1d could be a valuable marker for further therapeutic evaluation of human monocytic MDSCs for immune-related diseases, including GVHD.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2023

Structural insights into protection against a SARS-CoV-2 spike variant by T cell receptor diversity

T cells play a crucial role in combatting SARS-CoV-2 and forming long-term memory responses to this coronavirus. The emergence of SARS-CoV-2 variants that can evade T cell immunity has raised concerns about vaccine efficacy and the risk of reinfection. Some SARS-CoV-2 T cell epitopes elicit clonally restricted CD8 + T cell responses characterized by T cell receptors (TCRs) that lack structural diversity. Mutations in such epitopes can lead to loss of recognition by most T cells specific for that epitope, facilitating viral escape. Here, we studied an HLA-A2–restricted spike protein epitope (RLQ) that elicits CD8 + T cell responses in COVID-19 convalescent patients characterized by highly diverse TCRs. We previously reported the structure of an RLQ-specific TCR (RLQ3) with greatly reduced recognition of the most common natural variant of the RLQ epitope (T1006I). Opposite to RLQ3, TCR RLQ7 recognizes T1006I with even higher functional avidity than the WT epitope. To explain the ability of RLQ7, but not RLQ3, to tolerate the T1006I mutation, we determined structures of RLQ7 bound to RLQ–HLA-A2 and T1006I–HLA-A2. These complexes show that there are multiple structural solutions to recognizing RLQ and thereby generating a clonally diverse T cell response to this epitope that assures protection against viral escape and T cell clonal loss.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2022

Immunogenicity and therapeutic targeting of a public neoantigen derived from mutated PIK3CA

Public neoantigens (NeoAgs) represent an elite class of shared cancer-specific epitopes derived from recurrently mutated driver genes. Here we describe a high-throughput platform combining single-cell transcriptomic and T cell receptor (TCR) sequencing to establish whether mutant PIK3CA, among the most frequently genomically altered driver oncogenes, generates an immunogenic public NeoAg. Using this strategy, we developed a panel of TCRs that recognize an endogenously processed neopeptide encompassing a common PIK3CA hotspot mutation restricted by the prevalent human leukocyte antigen (HLA)-A*03:01 allele. Mechanistically, immunogenicity to this public NeoAg arises from enhanced neopeptide/HLA complex stability caused by a preferred HLA anchor substitution. Structural studies indicated that the HLA-bound neopeptide presents a comparatively ‘featureless’ surface dominated by the peptide’s backbone. To bind this epitope with high specificity and affinity, we discovered that a lead TCR clinical candidate engages the neopeptide through an extended interface facilitated by an unusually long CDR3β loop. In patients with diverse malignancies, we observed NeoAg clonal conservation and spontaneous immunogenicity to the neoepitope. Finally, adoptive transfer of TCR-engineered T cells led to tumor regression in vivo in mice bearing PIK3CA-mutant tumors but not wild-type PIK3CA tumors. Together, these findings establish the immunogenicity and therapeutic potential of a mutant PIK3CA-derived public NeoAg.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

sNebula, a network-based algorithm to predict binding between human leukocyte antigens and peptides

Understanding the binding between human leukocyte antigens (HLAs) and peptides is important to understand the functioning of the immune system. Since it is time-consuming and costly to measure the binding between large numbers of HLAs and peptides, computational methods including machine learning models and network approaches have been developed to predict HLA-peptide binding. However, there are several limitations for the existing methods. We developed a network-based algorithm called sNebula to address these limitations. We curated qualitative Class I HLA-peptide binding data and demonstrated the prediction performance of sNebula on this dataset using leave-one-out cross-validation and five-fold cross-validations. Furthermore, this algorithm can predict not only peptides of different lengths and different types of HLAs, but also the peptides or HLAs that have no existing binding data. We believe sNebula is an effective method to predict HLA-peptide binding and thus improve our understanding of the immune system.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2017

How an alloreactive T-cell receptor achieves peptide and MHC specificity

T-cell receptor (TCR) allorecognition is often presumed to be relatively nonspecific, attributable to either a TCR focus on exposed major histocompatibility complex (MHC) polymorphisms or the degenerate recognition of allopeptides. However, paradoxically, alloreactivity can proceed with high peptide and MHC specificity. Although the underlying mechanisms remain unclear, the existence of highly specific alloreactive TCRs has led to their use as immunotherapeutics that can circumvent central tolerance and limit graft-versus-host disease. Here, we show how an alloreactive TCR achieves peptide and MHC specificity. The HCV1406 TCR was cloned from T cells that expanded when a hepatitis C virus (HCV)-infected HLA-A2 - individual received an HLA-A2 + liver allograft. HCV1406 was subsequently shown to recognize the HCV nonstructural protein 3 (NS3):1406–1415 epitope with high specificity when presented by HLA-A2. Our research shows that NS3/HLA-A2 recognition by the HCV1406 TCR is critically dependent on features unique to both the allo-MHC and the NS3 epitope. We also find cooperativity between structural mimicry and a crucial peptide “hot spot” and demonstrate its role, along with the MHC, in directing the specificity of allorecognition. Our results help explain the paradox of specificity in alloreactive TCRs and have implications for their use in immunotherapy and related efforts to manipulate TCR recognition, as well as alloreactivity in general.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

NASA NTRS1978

Study of Civil Markets for Heavy-Lift Airships

The civil markets for heavy lift airships (HLAs) were defined by first identifying areas of most likely application. The operational suitability of HLAs for the applications identified were then assessed. The operating economics of HLAs were established and the market size for HLA services estimated by comparing HLA operating and economic characteristics with those of competing modes. The sensitivities of the market size to HLA characteristics were evaluated and the number and sizes of the vehicles required to service the more promising markets were defined. Important characteristics for future HLAs are discussed that were derived from the study of each application, including operational requirements, features enhancing profitability, military compatibility, improved design requirements, approach to entry into service, and institutional implications for design and operation.

Mettam, P. J.↗

NASA NTRS1980

Generic multi-body formulation of heavy lift airship equations of motion

This paper describes the formulation of a comprehensive set of equations which describe the dynamic behavior of a generic heavy lift airship (HLA). They are being used in a digital computer simulation to investigate the response dynamics and flying qualities of HLAs operating with various payloads in a variety of operational environments. A key feature is the separate treatment of each component body making up the HLA. This allows the analyst to vary the configuration (e.g., number of lift-propulsion units, presence or absence of slung payload, etc.) without rewriting the equations. It further provides measures of key structural and control loads acting on the HLA and eases the task of modeling wind disturbances.

Ringland, R. F.↗

NASA NTRS1983

Heavy-lift airship dynamics

The basic aerodynamic and dynamic properties of an example heavy-lift airship (HLA) configuration are analyzed using a nonlinear, multibody, 6-degrees-of-freedom digital simulation. The slung-payload model is described, and a preliminary analysis of the coupled vehicle-payload dynamics is presented. Trim calculations show the importance of control mixing selection and suggest performance deficiencies in crosswind stationkeeping for the unloaded example HLA. Numerically linearized dynamics of the unloaded vehicle exhibit a divergent yaw mode and an oscillatory pitch mode whose stability characteristic is sensitive to flight speed. An analysis of the vehicle-payload dynamics shows significant coupling of the payload dynamics with those of the basic HLA. It is shown that significant improvement in the vehicle's dynamic behavior can be achieved with the incorporation of a simple flight controller having proportional, rate, and integral-error feedbacks.

Tischler, M. B.↗

NASA NTRSDate not supplied

Using Open Standards and NASA Open Source Simulation Tools to Model Artemis Base Camp Mission Timelines

The United States’ National Aeronautics and Space Administration (NASA) has announced that the Artemis Program will return humans to the Moon, establishing a persistent presence with the Artemis Base Camp (ABC), and extend human exploration to Mars. The NASA Exploration Systems Simulations (NExSyS) team at NASA’s Johnson Space Center is using internationally developed simulation interoperability standards and NASA open source simulation tools to support Artemis concept, analysis, designs, development, training, and ultimately operations. The NExSyS team has been tasked to support early ABC architecture and mission analysis using mission time lines developed by the crew operations mission planning team. The NExSyS team is developing a distributed simulation framework with initial Artemis element implementations to model the ABC mission timelines using the international simulation interoperability standard High Level Architecture (HLA), the Simulation Interoperability Standards Organization’s Space Reference Federation Object Model (SpaceFOM), the NASA open source Trick Simulation Environment, and another NASA open source interface package called TrickHLA. The ABC architecture is composed of a number of key surface elements and resources. Some examples of modeled elements (also known as entities) are landers, habitats, rovers, logistics carriers, and astronauts. Some examples of modeled transferable and consumable resources are power, water, oxygen, nitrogen, scientific samples, and food. These entities and resources are modeled in a collection of individual simulations called Federates. A coordinated collection of interoperable federates is called a Federation and when these federates are tied together in a coordinated simulation run, it is referred to as a Federation Execution. The federates communicate through HLA using data exchange formats defined by a collection of machine readable files called Federation Object Models (FOMs). These FOM files are based on extensions to the SpaceFOM. This enables the instantiation and sharing of objects and interactions between federates in the federation. These provide for entity and resource tracking, object transfer, and data collection. Federate interactions are used to trigger events and notify federates of entity or resource transfers. For the initial implementation, the constituent federates are Trick-based simulations that use TrickHLA to provide the required HLA-base interoperability. These Trick-based simulations provide the required modeling for the individual Artemis elements along with the associated element resources. These federates provide a means to explore traverses between surface elements and exploration sites as scheduled in a mission timeline and explore the affects traverse times have on the overall mission timeline. The mission time lines are modeled using a Trick input file event handling capabilities. Each timeline operation is handled as individual simulation events, and triggered based on previous event status, time of operation, and simulated task completions. In addition, the ABC Federation can be used to perform Monte Carlo analysis. The Monte Carlo tool can vary the inputs, timings, and malfunctions to show how various contingencies in the mission can affect the mission timeline.

Keaton Craig Dodd↗

NASA NTRSDate not supplied

SpaceFOM: An Interoperability Standard for Space Systems Simulations

There is a long history of simulation supporting space systems development. This includes relatively simple parametric simulations to more complex trajectory simulations to large scale integrated vehicle simulation. One area of relatively recent development is in the area of distributed or interoperable simulation. Distributed simulation has been in wide use by the US military for years but is being used more widely in the aerospace community. To support large scale distributed simulation, the military community has developed a number of standards to support a priori interoperability between large collections of disparate simulation. For example, the IEEE 1516 High Level Architecture (HLA) and the Real-time Platform Reference Federation Object Model (RPR FOM). While HLA is suitable for space systems, there are a number of design decisions made in the development of the RPR FOM that prevent it from working well for space applications. In order to address these deficiencies, the Simulation Interoperability Standards Organization (SISO) developed a new HLS-compatible interoperability standard to support the needs of complex space systems. This standard is the Space Reference Federation Object Model (SpaceFOM). This paper presents on overview of the SpaceFOM including the fundamentals of the SpaceFOM, the key features of the SpaceFOM, and how the SpaceFOM supports large scale distributed simulation of complex space systems.

SISO↗

NASA NTRSDate not supplied

Development of the Artemis Distributed Simulation FOMs

The National Aeronautics and Space Administration (NASA) is formulating and developing the Artemis Program, a collaboration with domestic commercial and international partners that will establish a long term human presence on the Moon and extend human exploration beyond the Earth-Moon system ahead of exploring Mars. These Artemis partners are developing a portfolio of space and surface systems to support human missions to the lunar surface and beyond. The Artemis systems will provide the mobility, habitation, and logistics infrastructure that will support human exploration and foster robust scientific investigations. Each partner will contribute one or more elements to the Artemis Program with NASA having the overarching responsibility for defining the Artemis architecture and guiding the integration of this complex system of space systems. To successfully accomplish this audacious task, NASA will rely on the development and execution of many complex models and simulations. Many of these simulations will be provided by the Artemis partners. While each of these simulations will provide important insight into the characteristics and performance of an associated system, individually they will not provide insight into the integrated performance of the architecture and the system of systems working in concert to execute a given Artemis mission. To address this need, NASA is developing a distributed simulation capability called the Artemis Distributed Simulation (ADS). ADS’s distributed nature supports the complex aggregation of constituent Artemis element simulations. Artemis partner simulations will be able to join into an ADS-based distributed simulation and interact with other Artemis element simulations while limiting the exposure of proprietary designs and data. ADS is defining a distributed simulation capability built on international simulation interoperability standards, specifically the High Level Architecture (HLA) and the Space Reference Federation Object Model (SpaceFOM). While HLA and SpaceFOM provide the substantive necessary technology basis for ADS, additional common datatypes, message definitions, and execution protocols are required. These extensions constitute the ADS Federation Object Model (FOM). This paper describes the fundamental architectural elements of ADS and the FOM extensions needed to support the complex nature of the Artemis Program. This includes the examination of the ADS FOM modules, ADS base datatypes, ADS SpaceFOM Object Class extensions, new ADS Object Classes, and new ADS Interaction Classes.

HLA↗

NASA NTRSDate not supplied

Development of the Artemis Distributed Simulation FOMs

HLA↗

DOE OSTI2018

Mutant cytoskeletal and ECM peptides sensitive to the ST14 protease are associated with a worse outcome for glioblastoma multiforme

Highlights: • In GBM, mutant ECM proteins appear largely resistant to the ST14 protease. • Patients with resistant proteins have a better survival. • The few patients with sensitive mutants have T-cell infiltrates. We previously identified a set of the most frequently mutated cytoskeleton- and extracellular matrix-related proteins (CECMPs) in numerous cancer datasets. In this report, we used a bioinformatics approach to assess the impact of amino acid (AA) substitutions on the sensitivity of CECMPs to the ST14 protease (matriptase I), a transmembrane serine protease previously implicated in cancer development. Results indicated that AA substitutions in glioblastoma multiforme (GBM) CECMPs are skewed toward increased resistance to the ST14 protease, in comparison to the wild-type peptide sequence. Furthermore, the protease resistant AA substitutions represent relatively high binding affinities to HLA class I proteins, when assessing the binding specificities using HLA class I alleles matched to the source of the mutant AA. Moreover, samples representing AA substitutions that increased protease sensitivity also represented reduced overall and disease-free survival periods for patients with glioblastoma. To assess tumor specimen immunogenicity, we identified T-cell receptor (TCR) V(D)J recombinations in GBM exome files. The overlap between ST14 protease sensitive mutant barcodes and the TCR V(D)J recombination read positive barcodes represented significantly reduced survival.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2021

Dendritic cells focus CTL responses toward highly conserved and topologically important HIV-1 epitopes

During early HIV-1 infection, immunodominant T cell responses to highly variable epitopes lead to the establishment of immune escape virus variants. Here we assessed a type 1-polarized monocyte-derived dendritic cell (MDC1)-based approach to selectively elicit cytotoxic T lymphocyte (CTL) responses against highly conserved and topologically important HIV-1 epitopes in HIV-1-infected individuals from the Thailand RV254/SEARCH 010 cohort who initiated antiretroviral therapy (ART) during early infection (Fiebig stages I-IV). Autologous MDC1 were used as antigen presenting cells to induce in vitro CTL responses against HIV-1 Gag, Pol, Env, and Nef as determined by flow cytometry and ELISpot assay. Ultra-conserved or topologically important antigens were respectively identified using the Epigraph tool and a structure-based network analysis approach and compared to overlapping peptides spanning the Gag proteome. MDC1 presenting either the overlapping Gag, Epigraph, or Network 14-21mer peptide pools consistently activated and expanded HIV-1-specific T cells to epitopes identified at the 9-13mer peptide level. Interestingly, some CTL responses occurred outside known or expected HLA associations, providing evidence of new HLA-associated CTL epitopes. Comparative analyses demonstrated more sequence conservation among Epigraph antigens but a higher magnitude of CTL responses to Network and Gag peptide groups. Importantly, CTL responses against topologically constrained Gag epitopes contained in both the Network and Gag peptide pools were selectively enhanced in the Network pool-initiated cultures. Our study supports the use of MDC1 as a therapeutic strategy to induce and focus CTL responses toward putative fitness-constrained regions of HIV-1 to prevent immune escape and control HIV-1 infection.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

The Total Body Irradiation Schedule Affects Acute Leukemia Relapse After Matched T Cell–Depleted Hematopoietic Stem Cell Transplantation

Purpose: We sought to determine whether the total body irradiation (TBI) schedule affected outcome in patients with acute leukemia in complete remission who received T cell–depleted allogeneic hematopoietic stem cell transplantation from HLA identical siblings. Methods and Materials: The study recruited 55 patients (median age, 48 years; age range, 20-66 years; 30 men and 25 women; 34 with acute myeloid leukemia and 21 with acute lymphoid leukemia). Hyperfractionated TBI (HTBI) (1.2 Gy thrice daily for 4 days [for a total dose of 14.4 Gy] from day −12 to day −9) was administered to 29 patients. Single-dose TBI (STBI) (8 Gy, at a median dose rate of 10.7 cGy/min on day −9) was given to 26 patients. Results: All patients achieved primary, sustained engraftment with full donor-type chimerism. At 10 years, the overall cumulative incidence of transplant-related mortality was 11% (SE, ±0.1%). It was 7% (SE, ±0.2%) after HTBI and 15% (SE, ±0.5%) after STBI (P=.3). The overall cumulative incidence of relapse was 33% (SE, ±0.5). It was 13% (SE, ±0.5%) after HTBI and 46% (SE, ±1%) after STBI (P=.02). The overall probability of disease-free survival (DFS) was 59% (SE, ±7%). It was 67% (SE, ±0.84%) after HTBI and 37% (SE, ±1.4%) after STBI (P=.01). Multivariate analyses showed the TBI schedule was the only risk factor that significantly affected relapse and DFS (P=.01 and P=.03, respectively). Conclusions: In patients with acute leukemia, HTBI is more efficacious than STBI in eradicating minimal residual disease after HLA-matched T cell–depleted hematopoietic stem cell transplantation, thus affecting DFS.

62 RADIOLOGY AND NUCLEAR MEDICINE↗

DOE OSTI2017

Using DR52c/Ni{sup 2+} mimotope tetramers to detect Ni{sup 2+} reactive CD4{sup +} T cells in patients with joint replacement failure

T cell mediated hypersensitivity to nickel (Ni{sup 2+}) is one of the most common causes of allergic contact dermatitis. Ni{sup 2+} sensitization may also contribute to the failure of Ni{sup 2+} containing joint implants, and revision to non-Ni{sup 2+} containing hardware can be costly and debilitating. Previously, we identified Ni{sup 2+} mimotope peptides, which are reactive to a CD4{sup +} T cell clone, ANi2.3 (Vα1, Vβ17), isolated from a Ni{sup 2+} hypersensitive patient with contact dermatitis. This T cell is restricted to the major histocompatibility complex class II (MHCII) molecule, Human Leukocyte Antigen (HLA)-DR52c (DRA, DRB3*0301). However, it is not known if Ni{sup 2+} induced T cell responses in sensitized joint replacement failure patients are similar to subjects with Ni{sup 2+} induced contact dermatitis. Here, we generated DR52c/Ni{sup 2+} mimotope tetramers, and used them to test if the same Ni{sup 2+} T cell activation mechanism could be generalized to Ni{sup 2+} sensitized patients with associated joint implant failure. We confirmed the specificity of these tetramers by staining of ANi2.3 T cell transfectomas. The DR52c/Ni{sup 2+} mimotope tetramer detected Ni{sup 2+} reactive CD4{sup +} T cells in the peripheral blood mononuclear cells (PBMC) of patients identified as Ni{sup 2+} sensitized by patch testing and a positive Ni{sup 2+} LPT. When HLA-typed by a DR52 specific antibody, three out of four patients were DR52 positive. In one patient, Ni{sup 2+} stimulation induced the expansion of Vβ17 positive CD4{sup +} T cells from 0.8% to 13.3%. We found that the percentage of DR52 positivity and Vβ17 usage in Ni{sup 2+} sensitized joint failure patients are similar to Ni sensitized skin allergy patients. Ni{sup 2+} independent mimotope tetramers may be a useful tool to identify the Ni{sup 2+} reactive CD4{sup +} T cells. - Highlight: • Nickel hypersensitive patients with implant failure are dominantly DR52 positive. • These patients may have similar TCR beta chain usage to that of contact dermatitis. • The nickel mimotope tetramers are a tool to identify the nickel reactive CD4{sup +} T cells.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2014

Chimeric SV40 virus-like particles induce specific cytotoxicity and protective immunity against influenza A virus without the need of adjuvants

Virus-like particles (VLPs) are a promising vaccine platform due to the safety and efficiency. However, it is still unclear whether polyomavirus-based VLPs are useful for this purpose. Here, we attempted to evaluate the potential of polyomavirus VLPs for the antiviral vaccine using simian virus 40 (SV40). We constructed chimeric SV40-VLPs carrying an HLA-A{sup ⁎}02:01-restricted, cytotoxic T lymphocyte (CTL) epitope derived from influenza A virus. HLA-A{sup ⁎}02:01-transgenic mice were then immunized with the chimeric SV40-VLPs. The chimeric SV40-VLPs effectively induced influenza-specific CTLs and heterosubtypic protection against influenza A viruses without the need of adjuvants. Because DNase I treatment of the chimeric SV40-VLPs did not disrupt CTL induction, the intrinsic adjuvant property may not result from DNA contaminants in the VLP preparation. In addition, immunization with the chimeric SV40-VLPs generated long-lasting memory CTLs. We here propose that the chimeric SV40-VLPs harboring an epitope may be a promising CTL-based vaccine platform with self-adjuvant properties. - Highlights: • We constructed chimeric SV40-VLPs carrying an influenza virus-derived CTL epitope. • Chimeric SV40-VLPs induce influenza-specific CTLs in mice without adjuvants. • Chimeric SV40-VLPs induce heterosubtypic protection against influenza A viruses. • Chimeric SV40-VLPs induce long-lasting memory CTLs. • Chimeric SV40-VLPs is a promising vaccine platform with self-adjuvant properties.

60 APPLIED LIFE SCIENCES↗

DOE OSTI2016

MHC class II complexes sample intermediate states along the peptide exchange pathway

The presentation of peptide-MHCII complexes (pMHCIIs) for surveillance by T cells is a well-known immunological concept in vertebrates, yet the conformational dynamics of antigen exchange remain elusive. By combining NMR-detected H/D exchange with Markov modelling analysis of an aggregate of 275 microseconds molecular dynamics simulations, we reveal that a stable pMHCII spontaneously samples intermediate conformations relevant for peptide exchange. More specifically, we observe two major peptide exchange pathways: the kinetic stability of a pMHCII’s ground state defines its propensity for intrinsic peptide exchange, while the population of a rare, intermediate conformation correlates with the propensity of the HLA-DM-catalysed pathway. Helix-destabilizing mutants designed based on our model shift the exchange behaviour towards the HLA-DM-catalysed pathway and further allow us to conceptualize how allelic variation can shape an individual’s MHC restricted immune response.

59 BASIC BIOLOGICAL SCIENCES↗