How CD4+ T Cells Recognize Allostimulatory Peptide-MHC

Critical in determining transplantation outcome, whether tolerance is achieved or not, are CD4+ T cells that can recognize peptides presented on allogeneic (non-self) Major Histocompatibility Complex (MHC) molecules in addition to their conventional ligands, peptides presented on self MHC. It is an enigma as to how these alloreactive T cells can bind to allogeneic MHC given that T cells undergo stringent positive selection during development to bind to peptides presented on self MHC. We hypothesize that T cells bind to peptides on non-self MHC using the same properties involved in binding their conventional ligands. We identified allostimulatory peptide-MHC (pMHC) ligands (I-Ek as the allogeneic MHC) for two LLO/I-Ab-specific CD4+ T cells, LLO118 and 1G5.1. Both T cells recognized their allostimulatory ligand with a high degree of specificity and sensitivity for the allopeptide, similar to how they recognized their cognate ligand. Allopeptide recognition was also shown to not merely reflect mimicry of the cognate peptide. The integral role of the peptide in alloreactivity was further confirmed by the ability to convert previously non-alloreactive T cell hybrids into becoming responsive with the addition of peptide pools. In addition, the binding affinity and kinetics of LLO118 to its allostimulatory and cognate pMHC ligands were compared using surface plasmon resonance (Biacore system). LLO118 bound its alloligand using similar affinity and kinetics compared to its cognate ligand. In comparing alloreactivity with conventional recognition, which has not been done before for CD4+ T cells, we have found that similar peptide specificity and binding affinity are used to recognize both ligands, shedding light on the fundamental binding properties of the T cell receptor (TCR) for pMHC. Within the population of alloreactive T cells, a significant percentage is comprised of dual TCR T cells. This occurs from incomplete allelic exclusion of the TCRα loci during thymic development, allowing for simultaneous rearrangement of TCRα on both alleles until positively selecting signals are received through the TCR. In dual TCR T cells, only one TCR needs to mediate positive selection, and an autoreactive TCR can be masked from negative selection through decreased surface expression. This generates a repertoire of T cells containing secondary TCRs unconstrained by thymic selection. We set out to investigate the impact of secondary TCRα rearrangement to determine what benefit this has on thymic development and further define its contribution to peripheral T cell responses. Our hypothesis is that secondary TCRα rearrangement positively impacts the development of T cells, but atypical TCR properties that arise contribute to alloreactivity and autoimmunity. We examined mice heterozygous for the T cell receptor α chain constant region (TCRα+/-), which have only one functional TCRα rearrangement. The mice had a defect in generating mature T cells attributable to decreased positive selection. Elimination of secondary TCRs did not broadly alter the peripheral T cell compartment, though deep sequencing of the TCRα repertoire demonstrated unique TCRs resulting from secondary rearrangements. The functional consequence of these unique TCRs was evidenced by the significantly reduced frequencies of TCRα+/- T cell binding to autoantigen and alloantigen pMHC tetramers as well as decreased in vivo alloreactivity. Analysis of responses to altered peptide ligands (APLs) revealed that dual TCR T cells had increased flexibility in their recognition of allogeneic ligands, indicating a mechanism for their importance in alloreactivity. Our results show that the role of secondary TCRs in alloreactivity appears to be more significant than what has been assumed. Another factor we wanted to investigate in alloreactivity - as well as in autoimmunity and conventional T cell responses - is the effect of MHC composition, specifically the impact of increasing the types of MHC molecules expressed. It is perplexing why vertebrates express a limited number of MHC molecules when theoretically, having a greater repertoire of MHC molecules would increase the number of epitopes presented, thereby enhancing thymic selection and T cell response to pathogens. It is possible that any positive effects would either be neutralized or outweighed by negative selection restricting the T cell repertoire. We hypothesize that the limit on MHC number is due to negative consequences arising from expressing additional MHC. We compared T cell responses between B6 mice (I-A+) and B6.E+ mice (I-A+, I-E+), the latter expressing a second class II MHC molecule, I-Eb. The naive TCR Vβ repertoire was altered in B6.E+ thymi and spleens, suggesting a potential for mediating different outcomes in T cell reactivity. In alloreactivity, the B6.E+ T cell response was significantly dampened. We wondered if similar effects would be seen in other types of immune responses. The B6 and B6.E+ responses to hen egg-white lysozyme (HEL) protein immunization remained similar, but the quality of the T cell response was subtly altered in viral infection and there was markedly enhanced susceptibility to experimental autoimmune encephalomyelitis (EAE) in B6.E+ mice. The EAE phenotype could be explained by decreased percentage of natural regulatory T cells (nTregs) in the B6.E+ mice. Our data suggest that expressing an additional class II MHC can produce both positive and negative effects on a wide range of T cell responses. In conclusion, new insight into CD4+ T cell alloreactivity has been gained, with our research indicating that specificity of peptide binding, weak affinity, flexibility in recognition by dual TCR T cells, and MHC composition all contribute significantly to allorecognition

Evaluation Capacity-Building For A 'Migrant Children-Focused' Service

Special Studies Experience, Summer 2016 -- Xi'an City, China -- Partner Agencie(s): Shaanxi Xiaoci Social Development Centerhttp://deepblue.lib.umich.edu/bitstream/2027.42/134326/1/Poster_Cherylene_Aw_Peini_Ong.pd

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In this paper, we demonstrate a new ultra-wideband (UWB) localization testbed, which tracks a UWB tag and estimates locations of obstacles based on channel impulse response measurements. Anchor nodes that are developed with off-the-shelf Decawave DW1000 UWB transceivers are deployed to cover the area of interest. The testbed is implemented and preliminary experiments are carried out to estimate the location of the object by analyzing channel impulse response strength of the UWB tag.This work was partially supported by National Funds through FCT/MCTES (Portuguese Foundation for Science and Technology), within the CISTER Research Unit (UIDP/UIDB/04234/2020); also by the Operational Competitiveness Programme and Internationalization (COMPETE 2020) under the PT2020 Partnership Agreementinfo:eu-repo/semantics/publishedVersio

Who's in charge? Discovering the autonomy in an institutional data repository for research data curation and sharing

To facilitate data sharing, more and more research data infrastructures have been built. However, less attention is paid to the needs of researchers as data producers in the context of traditional OAIS-compliant institutional data repositories. Meanwhile, researchers usually complete data management tasks themselves throughout the research data lifecycle and express a desire to control the data ingestion process. The contradictory between design and the reality suggests a potential need for autonomy in terms of data curation along with frictions between researchers and professional data curators. In this study, we explore important features of an ideal institutional data repository through designing the NTUData prototype. It is a researcher-centered system that helps integrate the early phases of the data lifecycle into the process of data curation and thus encourage data sharing. Nine participants in the information science field were recruited for a usability test in which the DCP Toolkit was adopted. The results show that researchers prefer to initiate and perform the whole data submission process themselves. They are also concerned about the interoperability to link NTUData to external resources and the interpretability of text labels within this repository. As for their needs towards autonomy, two per- spectives with regards to curating and sharing data can be observed, respectively

An Evacuation Model for Passenger Ships That Includes the Influence of Obstacles in Cabins

Passenger behavior and ship environment are the key factors affecting evacuation efficiency. However, current studies ignore the interior layout of passenger ship cabins and treat the cabins as empty rooms. To investigate the influence of obstacles (e.g., tables and stools) on cabin evacuation, we propose an agent-based social force model for advanced evacuation analysis of passenger ships; this model uses a goal-driven submodel to determine a plan and an extended social force submodel to govern the movement of passengers. The extended social force submodel considers the interaction forces between the passengers, crew, and obstacles and minimises the range of these forces to improve computational efficiency. We drew the following conclusions based on a series of evacuation simulations conducted in this study: (1) the proposed model endows the passenger with the behaviors of bypassing and crossing obstacles, (2) funnel-shaped exits from cabins can improve evacuation efficiency, and (3) as the exit angle increases, the evacuation time also increases. These findings offer ship designers some insight towards increasing the safety of large passenger ships

Paradigm shift in determining Neoproterozoic atmospheric oxygen

ACKNOWLEDGMENTS We thank the Geological Survey of Australia for permission to sample the Empress 1A and Lancer 1 cores, the Natural Sciences and Engineering Research Council of Canada for financial support (grant #7961–15) of U. Brand, and the National Natural Science Foundation of China for support of F. Meng and P. Ni (grants 41473039 and 4151101015). We thank M. Lozon (Brock University) for drafting and constructing the figures. We thank the editor, Brendan Murphy, as well as three reviewers (Steve Kesler, Erik Sperling, and an anonymous reviewer), for improving the manuscript into its final form.Peer reviewedPublisher PD

Gold on graphene as a substrate for surface enhanced Raman scattering study

In this paper, we report our study on gold (Au) films with different thicknesses deposited on single layer graphene (SLG) as surface enhanced Raman scattering (SERS) substrates for the characterization of rhodamine (R6G) molecules. We find that an Au film with a thickness of ~7 nm deposited on SLG is an ideal substrate for SERS, giving the strongest Raman signals for the molecules and the weakest photoluminescence (PL) background. While Au films effectively enhance both the Raman and PL signals of molecules, SLG effectively quenches the PL signals from the Au film and molecules. The former is due to the electromagnetic mechanism involved while the latter is due to the strong resonance energy transfer from Au to SLG. Hence, the combination of Au films and SLG can be widely used in the characterization of low concentration molecules with relatively weak Raman signals.Comment: 11 pages, 4 figure

Introduction to the thematic issue: Mineral deposits exploration and environmental geochemistry: case studies in Italy and in China

Raw materials are fundamental to the economy, and hence to growth and jobs, and they are essential for maintaining and improving our quality of life. Securing reliable, sustainable and economic access to certain 'critical' raw materials is of growing concern around the globe. But it is as well a priority to acquire detailed information about the distribution of PTE and POP both at regional and local scales for environmental issues. The latter are of fundamental importance for environmental risk assessment and analysis that have a crucial role in the evaluation of human health risk, especially in mining and intensive urbanized areas. In addition, geochemical knowledge of the territory and mostly of top soils, where the main agricultural products grow, to become the foods for citizens, may be useful for land-use planning. Geochemical exploration methods are widely used to manage, visualize, analyse and interpret data for further identifying geochemical anomalies, for both the discovery of new ore bodies and for environmental purposes