118 research outputs found
Mafb lineage tracing to distinguish macrophages from other immune lineages reveals dual identity of Langerhans cells
Current systems for conditional gene deletion within mouse macrophage lineages are limited by ectopic activity or low efficiency. In this study, we generated a Mafb-driven Cre strain to determine whether any dendritic cells (DCs) identified by Zbtb46-GFP expression originate from a Mafb-expressing population. Lineage tracing distinguished macrophages from classical DCs, neutrophils, and B cells in all organs examined. At steady state, Langerhans cells (LCs) were lineage traced but also expressed Zbtb46-GFP, a phenotype not observed in any other population. After exposure to house dust mite antigen, Zbtb46-negative CD64(+) inflammatory cells infiltrating the lung were substantially lineage traced, but Zbtb46-positive CD64(−) cells were not. These results provide new evidence for the unique identity of LCs and challenge the notion that some inflammatory cells are a population of monocyte-derived DCs
Targeting of B and T lymphocyte associated (BTLA) prevents graft-versus-host disease without global immunosuppression
One-time treatment with an antibody against BTLA provides long-term protection against graft-versus-host disease without affecting effector T cell responses to tumors or pathogens
Zbtb46 expression distinguishes classical dendritic cells and their committed progenitors from other immune lineages
Distinguishing dendritic cells (DCs) from other cells of the mononuclear phagocyte system is complicated by the shared expression of cell surface markers such as CD11c. In this study, we identified Zbtb46 (BTBD4) as a transcription factor selectively expressed by classical DCs (cDCs) and their committed progenitors but not by plasmacytoid DCs (pDCs), monocytes, macrophages, or other lymphoid or myeloid lineages. Using homologous recombination, we replaced the first coding exon of Zbtb46 with GFP to inactivate the locus while allowing detection of Zbtb46 expression. GFP expression in Zbtb46(gfp/+) mice recapitulated the cDC-specific expression of the native locus, being restricted to cDC precursors (pre-cDCs) and lymphoid organ- and tissue-resident cDCs. GFP(+) pre-cDCs had restricted developmental potential, generating cDCs but not pDCs, monocytes, or macrophages. Outside the immune system, Zbtb46 was expressed in committed erythroid progenitors and endothelial cell populations. Zbtb46 overexpression in bone marrow progenitor cells inhibited granulocyte potential and promoted cDC development, and although cDCs developed in Zbtb46(gfp/gfp) (Zbtb46 deficient) mice, they maintained expression of granulocyte colony-stimulating factor and leukemia inhibitory factor receptors, which are normally down-regulated in cDCs. Thus, Zbtb46 may help enforce cDC identity by restricting responsiveness to non-DC growth factors and may serve as a useful marker to identify rare cDC progenitors and distinguish between cDCs and other mononuclear phagocyte lineages
Low B and T lymphocyte attenuator expression on CD4+ T cells in the early stage of sepsis is associated with the severity and mortality of septic patients: a prospective cohort study
Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8α+ conventional dendritic cells
Although CD103-expressing dendritic cells (DCs) are widely present in nonlymphoid tissues, the transcription factors controlling their development and their relationship to other DC subsets remain unclear. Mice lacking the transcription factor Batf3 have a defect in the development of CD8α(+) conventional DCs (cDCs) within lymphoid tissues. We demonstrate that Batf3(−/−) mice also lack CD103(+)CD11b(−) DCs in the lung, intestine, mesenteric lymph nodes (MLNs), dermis, and skin-draining lymph nodes. Notably, Batf3(−/−) mice displayed reduced priming of CD8 T cells after pulmonary Sendai virus infection, with increased pulmonary inflammation. In the MLNs and intestine, Batf3 deficiency resulted in the specific lack of CD103(+)CD11b(−) DCs, with the population of CD103(+)CD11b(+) DCs remaining intact. Batf3(−/−) mice showed no evidence of spontaneous gastrointestinal inflammation and had a normal contact hypersensitivity (CHS) response, despite previous suggestions that CD103(+) DCs were required for immune homeostasis in the gut and CHS. The relationship between CD8α(+) cDCs and nonlymphoid CD103(+) DCs implied by their shared dependence on Batf3 was further supported by similar patterns of gene expression and their shared developmental dependence on the transcription factor Irf8. These data provide evidence for a developmental relationship between lymphoid organ–resident CD8α(+) cDCs and nonlymphoid CD103(+) DCs
Open-label versus double-blind placebo treatment in irritable bowel syndrome: study protocol for a randomized controlled trial
Peripheral CD103+ dendritic cells form a unified subset developmentally related to CD8α+ conventional dendritic cells
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The effects of the cost of foreign internal funds on firms' financing choice of debt vs. internal funding
This paper examines how the multinational firm's choice of debt or internal funds as a method of financing depends upon the cost of using internal funds. I extend prior research by differentiating between the cost of using domestic versus foreign internal funds for additional investments for multinational enterprises. I predict that foreign funds are more costly than domestic funds because of potential differential costs, including repatriation tax costs and financial reporting costs. I find that my measure of total funds, the sum of cash and short-term receivables, is negatively related to issuing incremental debt. I also examine whether the proportion of total funds represented by foreign funds affects a firm's decision to use incremental debt financing. My proxy for foreign funds is a rough estimate using available Compustat data (foreign assets divided by total assets multiplied by total funds). I do not find significant results with this general measure of foreign funds. Additionally, I test whether firms' FTC positions affect incremental financing decisions. I do not find results with this measure of foreign funds. I further examine the impact of costly foreign funds on the incremental debt financing decision using alternative measures. I examine the differential costs of a subset of foreign funds with the designation and dollar level of permanently reinvested earnings. My results suggest that the change in debt is positively related to the dollar level of permanently reinvested earnings. In addition, in a model that includes the interaction between the dollar level of permanently reinvested earnings and non-binding FTC status, my results suggest that the magnitude of the relationship between the level of permanent reinvestment of foreign earnings and incremental debt financing is greater for firms with non-binding FTC limitations than for firms with binding FTC limitations. Overall, my findings suggest that the source of internal funds makes a difference in firms' use of debt financing. After controlling for investment opportunities with a measure of the difference between the foreign and domestic after-tax return, I find that financial reporting considerations impact the debt (versus internal funds) financing decision
Percutaneous absorption of topically-applied antiandrogens: an assessment with three independent methods
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