Cutting edge: unconventional CD8+ T cell recognition of a naturally occurring HLA-A*02:01-restricted 20mer epitope

Unconventional HLA class I-restricted CD8+ T cell epitopes, longer than 10 aa, have been implicated to play a role in human immunity against viruses and cancer. T cell recognition of long peptides, centrally bulging from the HLA cleft, has been described previously. Alternatively, long peptides can contain a linear HLA-bound core peptide, with a N- or C-terminal peptide "tail" extending from the HLA peptide binding groove. The role of such a peptide "tail" in CD8+ T cell recognition remains unclear. In this study, we identified a 20mer peptide (FLPTPEELGLLGPPRPQVLA [FLP]) derived from the IL-27R subunit α gene restricted to HLA-A*02:01, for which we solved the crystal structure and demonstrated a long C-terminal "tail" extension. FLP-specific T cell clones demonstrated various recognition modes, some T cells recognized the FLP core peptide, while for other T cells the peptide tail was essential for recognition. These results demonstrate a crucial role for a C-terminal peptide tail in immunogenicity. </p

Broadly applicable TCR-based therapy for multiple myeloma targeting the immunoglobulin J chain

Background: The immunoglobulin J chain (Jchain) is highly expressed in the majority of multiple myeloma (MM), and Jchain-derived peptides presented in HLA molecules may be suitable antigens for T-cell therapy of MM. Methods: Using immunopeptidomics, we identified Jchain-derived epitopes presented by MM cells, and pHLA tetramer technology was used to isolate Jchain-specific T-cell clones. Results: We identified T cells specific for Jchain peptides presented in HLA-A1, -A24, -A3, and -A11 that recognized and lysed JCHAIN-positive MM cells. TCRs of the most promising T-cell clones were sequenced, cloned into retroviral vectors, and transferred to CD8 T cells. Jchain TCR T cells recognized target cells when JCHAIN and the appropriate HLA restriction alleles were expressed, while JCHAIN or HLA-negative cells, including healthy subsets, were not recognized. Patient-derived JCHAIN-positive MM samples were also lysed by Jchain TCR T cells. In a preclinical in vivo model for established MM, Jchain-A1, -A24, -A3, and -A11 TCR T cells strongly eradicated MM cells, which resulted in 100-fold lower tumor burden in Jchain TCR versus control-treated mice. Conclusions: We identified TCRs targeting Jchain-derived peptides presented in four common HLA alleles. All four TCRs demonstrated potent preclinical anti-myeloma activity, encouraging further preclinical testing and ultimately clinical development.Proteomic

Upon opening the black box and finding it full : Exploring the ethics in design practices

Contemporary design practices, such as participatory design (PD), human-centered design (HCD), and codesign, have inherent ethical qualities, which often remain implicit and unexamined. Three design projects in the high-tech industry were studied using three ethical traditions as lenses. Virtue ethics helped to understand cooperation, curiosity, creativity, and empowerment as virtues that people in PD need to cultivate, so that they can engage, for example, in mutual learning and collaborative prototyping. Ethics of alterity (Levinas and Derrida) helped to understand human-centered design as a fragile encounter between project team members and prospective users, and foregrounds the ethics in these encounters: our tendencies to "grasp the other" and to "program invention." And pragmatist ethics (Dewey) helped to understand codesign as a process of joint inquiry and imagination, involving the organization of iterative processes of problemsetting and solution finding, with moral qualities. When we open the "black boxes" of design practices, we find them filled with ethics. Moreover, it is proposed that design practitioners need to make explicit their practices’ inherent ethical qualities and that they can do that by embracing reflexivity

High-tech meets end-user

One challenge within the high-tech sector is to develop products that end users will actually need and will be able to use. One way of trying to match the design of high-tech products to the needs of end users, is to let researchers and designers interact with them via a human-centred design (HCD) approach. One HCD project, in which the author works, is studied. It is shown that the relation between interacting with end users and making design decision is not straightforward or "logical." Gathering knowledge about end users is like making a grasping gesture and reduces their otherness. Making design decisions is not based on rationally applying rules. It is argued that doing HCD is a social process with ethical qualities. A role for management is suggested to organize HCD alternatively to stimulate researchers and designers to explicitly discuss such ethical qualities and to work more reflectively. © 2009, IGI Global

Virtues in participatory design : Cooperation, curiosity, creativity, empowerment and reflexivity

In this essay several virtues are discussed that are needed in people who work in participatory design (PD). The term PD is used here to refer specifically to an approach in designing information systems with its roots in Scandinavia in the 1970s and 1980s. Through the lens of virtue ethics and based on key texts in PD, the virtues of cooperation, curiosity, creativity, empowerment and reflexivity are discussed. Cooperation helps people in PD projects to engage in cooperative curiosity and cooperative creativity. Curiosity helps them to empathize with others and their experiences, and to engage in joint learning. Creativity helps them to envision, try out and materialize ideas, and to jointly create new products and services. Empowerment helps them to share power and to enable other people to flourish. Moreover, reflexivity helps them to perceive and to modify their own thoughts, feelings and actions. In the spirit of virtue ethics—which focuses on specific people in concrete situations—several examples from one PD project are provided. Virtue ethics is likely to appeal to people in PD projects because it is practice-oriented, provides room for exploration and experimentation, and promotes professional and personal development. In closing, some ideas for practical application, for education and for further research are discussed

Human-centered design as a fragile encounter

Many innovations in the information and communication technology (ICT) industry are driven by technological developments, rather than by concerns for users’ needs and preferences. This technology push approach brings a risk of creating products or services that people cannot or do not want to use. In some projects, however, people conduct human-centered design (HCD) as an alternative approach. In HCD, diverse experts, such as designers and researchers, cooperate with potential users—who are “experts of their experiences”1—to bring users’ ideas and knowledge into the innovation process and to jointly articulate problems and develop solutions

The fragility of human-centred design

In human-centred design (HCD), researchers and designers develop products in cooperation with the potential users of these products. They attempt to give users a voice or a role in their projects, with the intention of developing products that match users' needs and preferences. This approach is especially interesting in the information and communication technology (ICT) industry, in which many innovations are driven by development of technologies. The author works in HCD projects in the ICT industry and studied one particular project as a participant observer. In this project, two telecom applications were designed together with and for two groups of users: police officers and people who provide informal care. The resulting case studies are interpreted, drawing from the fields of design studies and science and technology studies, and using texts of the philosophers Levinas and Derrida. HCD is presented as a process that happens between people and as a process with ethical qualities. The case studies demonstrate that HCD is a worthwhile approach. They also show the difficulties of cooperating with users and of multi-disciplinary team-work. HCD practitioners attempt to be open towards others, but they also tend to move towards closure and towards the self. The author suggests reflexive practice as a way for practitioners to be more aware of and to articulate these tendencies. This is intended to help them to better align their practices with what HCD can be about: a process of learning and creating together.Industrial Design Engineerin