T cell epitope clustering in the highly immunogenic BZLF1 antigen of Epstein-Barr virus

Polymorphism in the human leukocyte antigen (HLA) loci ensures that the CD8 T cell response to viruses is directed against a diverse range of antigenic epitopes, thereby minimizing the impact of virus escape mutation across the population. The BZLF1 antigen of Epstein-Barr virus is an immunodominant target for CD8 T cells, but the response has been characterized only in the context of a limited number of HLA molecules due to incomplete epitope mapping. We have now greatly expanded the number of defined CD8 T cell epitopes from BZLF1, allowing the response to be evaluated in a much larger proportion of the population. Some regions of the antigen fail to be recognized by CD8 T cells, while others include clusters of overlapping epitopes presented by different HLA molecules. These highly immunogenic regions of BZLF1 include polymorphic sequences, such that up to four overlapping epitopes are impacted by a single amino acid variation common in different regions of the world. This focusing of the immune response to limited regions of the viral protein could be due to sequence similarity to human proteins creating "immune blind spots" through self-tolerance. This study significantly enhances the understanding of the immune response to BZLF1, and the precisely mapped T cell epitopes may be directly exploited in vaccine development and adoptive immunotherapy

Old Ways for New Days

This Open Access book provides a critical reflection into how indigenous cultures are attempting to adapt to climate change. Through detailed first-hand accounts, the book describes the unique challenges facing indigenous peoples in the context of climate change adaptation, governance, communication strategies, and institutional pressures. The book shows how current climate change terminologies and communication strategies often perpetuate the marginalisation of indigenous peoples and suggests that new approaches that prioritise Indigenous voices, agency and survival are required. The book first introduces readers to Indigenous peoples and their struggles related to climate change, describing the impacts of climate change on their everyday lives and the adaptation strategies currently undertaken to address them. These strategies are then detailed through case studies which focus on how Indigenous knowledge and practices have been used to respond to and cope with climate change in a variety of environments, including urban settings. The book discusses specific governance challenges facing Indigenous peoples, and presents new methods for engagement that will bridge existing communication gaps to ensure Indigenous peoples are central to the implementation of climate change adaptation measures. This book is intended for an audience of Indigenous peoples, adaptation practitioners, academics, students, policy makers and government workers. ; Documents for the first time how some of the world's oldest living indigenous cultures are attempting to adapt to climate change Summarizes key issues facing indigenous peoples in the context of adaptation to climate change impacts Offers critical reflection on specific governance challenges faced by indigenous people

Old Ways for New Days

This Open Access book provides a critical reflection into how indigenous cultures are attempting to adapt to climate change. Through detailed first-hand accounts, the book describes the unique challenges facing indigenous peoples in the context of climate change adaptation, governance, communication strategies, and institutional pressures. The book shows how current climate change terminologies and communication strategies often perpetuate the marginalisation of indigenous peoples and suggests that new approaches that prioritise Indigenous voices, agency and survival are required. The book first introduces readers to Indigenous peoples and their struggles related to climate change, describing the impacts of climate change on their everyday lives and the adaptation strategies currently undertaken to address them. These strategies are then detailed through case studies which focus on how Indigenous knowledge and practices have been used to respond to and cope with climate change in a variety of environments, including urban settings. The book discusses specific governance challenges facing Indigenous peoples, and presents new methods for engagement that will bridge existing communication gaps to ensure Indigenous peoples are central to the implementation of climate change adaptation measures. This book is intended for an audience of Indigenous peoples, adaptation practitioners, academics, students, policy makers and government workers. ; Documents for the first time how some of the world's oldest living indigenous cultures are attempting to adapt to climate change Summarizes key issues facing indigenous peoples in the context of adaptation to climate change impacts Offers critical reflection on specific governance challenges faced by indigenous people

Co-management and protected area management: Achieving effective management of a contested site, lessons from the Great Barrier Reef World Heritage Area (GBRWHA)

Marine protected management has gained acceptance as a way forward to achieve enhanced biodiversity outcomes. Simultaneously, co-management has gathered momentum as a mechanism to incorporate indigenous cultural aspirations within environmental management domains. Each management process has its own methodologies; when the two models intersect, they present a number of challenges to overall management outcomes. We review the journey of an indigenous co-management initiative within a marine protected area (MPA), the Great Barrier Reef World Heritage Area (GBRWHA), Australia, to explore how different management paradigms intersect with both negative and positive results. We argue that lessons learned from this initiative will help participants to adapt and innovate, so as to implement effective on ground management despite the region being a contested site.Co-management Indigenous Protected area management Australia Girringun

Interferon-γ production by tubulointerstitial human CD56bright natural killer cells contributes to renal fibrosis and chronic kidney disease progression

Natural killer (NK) cells are a population of lymphoid cells that play a significant role in mediating innate immune responses. Studies in mice suggest a pathological role for NK cells in models of kidney disease. In this study, we characterized the NK cell subsets present in native kidneys of patients with tubulointerstitial fibrosis, the pathological hallmark of chronic kidney disease. Significantly higher numbers of total NK cells (CD3CD56) were detected in renal biopsies with tubulointerstitial fibrosis compared with diseased biopsies without fibrosis and healthy kidney tissue using multi-color flow cytometry. At a subset level, both the CD56NK cell subset and particularly the CD56NK cell subset were elevated in fibrotic kidney tissue. However, only CD56NK cells significantly correlated with the loss of kidney function. Expression of the tissue-retention and -activation molecule CD69 on CD56NK cells was significantly increased in fibrotic biopsy specimens compared with non-fibrotic kidney tissue, indicative of a pathogenic phenotype. Further flow cytometric phenotyping revealed selective co-expression of activating receptor CD335 (NKp46) and differentiation marker CD117 (c-kit) on CD56NK cells. Multi-color immunofluorescent staining of fibrotic kidney tissue localized the accumulation of NK cells within the tubulointerstitium, with CD56NK cells (NKp46CD117) identified as the source of pro-inflammatory cytokine interferon-γ within the NK cell compartment. Thus, activated interferon-γ-producing CD56NK cells are positioned to play a key role in the fibrotic process and progression to chronic kidney disease

Hypoxic human proximal tubular epithelial cells undergo ferroptosis and elicit an NLRP3 inflammasome response in CD1c+ dendritic cells

Inflammasomes are multiprotein platforms responsible for the release of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. Mouse studies have identified inflammasome activation within dendritic cells (DC) as pivotal for driving tubulointerstitial fibrosis and inflammation, the hallmarks of chronic kidney disease (CKD). However, translation of this work to human CKD remains limited. Here, we examined the complex tubular cell death pathways mediating inflammasome activation in human kidney DC and, thus, CKD progression. Ex vivo patient-derived proximal tubular epithelial cells (PTEC) cultured under hypoxic (1% O2) conditions modelling the CKD microenvironment showed characteristics of ferroptotic cell death, including mitochondrial dysfunction, reductions in the lipid repair enzyme glutathione peroxidase 4 (GPX4) and increases in lipid peroxidation by-product 4-hydroxynonenal (4-HNE) compared with normoxic PTEC. The addition of ferroptosis inhibitor, ferrostatin-1, significantly reduced hypoxic PTEC death. Human CD1c+ DC activated in the presence of hypoxic PTEC displayed significantly increased production of inflammasome-dependent cytokines IL-1β and IL-18. Treatment of co-cultures with VX-765 (caspase-1/4 inhibitor) and MCC950 (NLRP3 inflammasome inhibitor) significantly attenuated IL-1β/IL-18 levels, supporting an NLRP3 inflammasome-dependent DC response. In line with these in vitro findings, in situ immunolabelling of human fibrotic kidney tissue revealed a significant accumulation of tubulointerstitial CD1c+ DC containing active inflammasome (ASC) specks adjacent to ferroptotic PTEC. These data establish ferroptosis as the primary pattern of PTEC necrosis under the hypoxic conditions of CKD. Moreover, this study identifies NLRP3 inflammasome signalling driven by complex tubulointerstitial PTEC-DC interactions as a key checkpoint for therapeutic targeting in human CKD.</p