GM-CSF Controls Nonlymphoid Tissue Dendritic Cell Homeostasis but Is Dispensable for the Differentiation of Inflammatory Dendritic Cells

SummaryGM-CSF (Csf-2) is a critical cytokine for the in vitro generation of dendritic cells (DCs) and is thought to control the development of inflammatory DCs and resident CD103+ DCs in some tissues. Here we showed that in contrast to the current understanding, Csf-2 receptor acts in the steady state to promote the survival and homeostasis of nonlymphoid tissue-resident CD103+ and CD11b+ DCs. Absence of Csf-2 receptor on lung DCs abrogated the induction of CD8+ T cell immunity after immunization with particulate antigens. In contrast, Csf-2 receptor was dispensable for the differentiation and innate function of inflammatory DCs during acute injuries. Instead, inflammatory DCs required Csf-1 receptor for their development. Thus, Csf-2 is important in vaccine-induced CD8+ T cell immunity through the regulation of nonlymphoid tissue DC homeostasis rather than control of inflammatory DCs in vivo

Mental Health in the Workplace: Unions' Role in Identifying and Combating Psychosocial Hazards

The world of paid work has shifted extraordinarily in the last several decades. Globalization, technology, lean production, the intensification of work, mergers and reorganizations and precarious work have all meant a toughening of the conditions for workers. Unions organize in these conditions, confronting issues of concern to workers. Very little has been written about the role unions play in trying to protect the psychological health of their members. The major question of this thesis is whether unions are identifying and combating psychosocial hazards in the workplace. The thesis adds to knowledge on this subject by analyzing two data sets. First I conduct an analysis of grey literature on the Internet about psychological health and safety concerns. Second, I explore a series of questions with union health and safety experts representing every major Canadian union from each sector of the economy. The questions probe how unions are dealing with psychosocial risks in the workplace, how unions are organizing resistance and building solidarity. My inquiry also explores the issue of how unions deal with return-to-work for workers who have been absent for mental health reasons. I am not a neutral observer: I write from the standpoint of workers. My work has a practical utility to the degree that it can be directly applied to these real life problems facing health and safety practitioners. It attempts to theorize that which these union specialists should do. It also tries to anticipate some practical problems they may need to solve in future as a result of current health and safety practices. I observe real life phenomena and develop theory around them. One of these is that unions resist employer restraints and power and in so doing bump up against managementsâ right to control production and dictate work organization. In this thesis, I show the fledgling ways in which unions are challenging managementsâ typical rights in the interests of better working conditions. I give evidence of three promising practices that unions are adopting and propose that these may be adapted further for initiatives in other sectors. I argue that workersâ psychological health is one potential winner of these strategies. I also propose that union representatives be educated to deal more empathically with members that are absent for reasons of psychological ill health, in advocating for them when they return and by building solidarity among co-workers.Ed.D

Human CD1c+ Dendritic Cells Drive the Differentiation of CD103+ CD8+ Mucosal Effector T Cells via the Cytokine TGF-β

In comparison to murine dendritic cells (DCs), less is known about the function of human DCs in tissues. Here, we analyzed, using lung tissues from humans and humanized mice, the role of human CD1c(+) and CD141(+) DCs in determining the type of CD8(+) T cell immunity generated to live-attenuated influenza virus (LAIV) vaccine. We found that both lung DC subsets acquired influenza antigens in vivo and expanded specific cytotoxic CD8(+) T cells in vitro. However, lung-tissue-resident CD1c(+) DCs but not CD141(+) DCs were able to drive CD103 expression on CD8(+) T cells and promoted CD8(+) T cell accumulation in lung epithelia in vitro and in vivo. CD1c(+) DCs induction of CD103 expression was dependent on membrane-bound cytokine TGF-β1. Thus, CD1c(+) and CD141(+) DCs generate CD8(+) T cells with different properties, and CD1c(+) DCs specialize in the regulation of mucosal CD8(+) T cells

Expression of Blimp-1 in Dendritic Cells Modulates the Innate Inflammatory Response in Dextran Sodium Sulfate-Induced Colitis

A single nucleotide polymorphism of PRDM1, the gene encoding Blimp-1, is strongly associated with inflammatory bowel disease. Here, we demonstrate that Blimp-1 in CD103(+) dendritic cells (DCs) critically contributes to the regulation of macrophage homeostasis in the colon. Dextran sodium sulfate (DSS)-exposed Blimp-1(cko) mice with a deletion of Blimp-1 in CD103(+) DCs and CD11c(hi) macrophages exhibited severe inflammatory symptoms, pronounced weight loss, high mortality, robust infiltration of neutrophils in epithelial regions of the colon, an increased expression of proinflammatory cytokines and a significant decrease in CD103(+) DCs in the colon compared with DSS exposed wild-type (WT) mice. Purified colonic macrophages from Blimp-1(cko) mice expressed increased levels of matrix metalloproteinase 8, 9 and 12 mRNA. WT macrophages cocultured with colonic DCs but not bone marrow-derived DCs from Blimp-1(cko) produced increased matrix metalloproteinases in an interleukin (IL)-1beta- and IL-6-dependent manner. Treatment of Blimp-1(cko) mice with anti-IL-1beta and anti-IL-6 abrogated the exaggerated clinical response. Overall, these data demonstrate that Blimp-1 expression in DCs can alter an innate inflammatory response by modulating the activation of myeloid cells. This is a novel mechanism of contribution of Blimp-1 for the pathogenesis of inflammatory bowel diseases, implicating another therapeutic target for the development of inflammatory bowel disease