CD28 expression is generally considered to be T lymphocyte specific. We have previously shown CD28 mRNA expression in M-CSF-dependent anti-inflammatory monocyte-derived macrophages (M-MØ), and now demonstrate that CD28 cell surface expression is higher in M-MØ than in GM-CSF-dependent macrophages, and that macrophage CD28 expression is regulated by MAFB and activin A. In vivo, CD28 was found in tumor-associated macrophages and, to a lower extent, in pro-inflammatory synovial fluid macrophages from rheumatoid arthritis patients. Analysis of mouse macrophages confirmed Cd28 expression in bone-marrow derived M-MØ. Indeed, anti-CD28 antibodies triggered ERK1/2 phosphorylation in mouse M-MØ. At the functional level, Cd28KO M-MØ exhibited a significantly higher capacity to activate the OVA-specific proliferation of OT-II CD4+ T cells than WT M-MØ, as well as enhanced LPS-induced IL-6 production. Besides, the Cd28KO M-MØ transcriptome was significantly different from WT M-MØ regarding the expression IFN response, inflammatory response, and TGF-β signaling related gene sets. Therefore, defective CD28 expression in mouse macrophages associates to changes in gene expression profile, what might contribute to the altered functionality displayed by Cd28KO M-MØ. Thus, CD28 expression appears as a hallmark of anti-inflammatory macrophages and might be a target for immunotherapy.
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Integrins are transmembrane receptors composed of one α subunit and one β subunit and are involved in cellular growth, differentiation, and apoptosis. The collagen-binding integrins α1β1 and α2β1 have been shown to regulate wound and tumor vascularization by different mechanisms. In this study, we assessed wound and tumor vascularization in mice with genetic ablation of both integrin subunits α1 and α2, which resulted in loss of integrins α1β1 and α2β1. Wound angiogenesis was investigated in excisional wounds that were inflicted on the back skin of control and mice lacking integrin α1β1 and α2β1. Mutant mice displayed reduced wound angiogenesis, which correlated with decreased macrophage numbers at 3 and 7 days after injury, and showed significantly attenuated vascularization of sponge implants. Angiogenesis induced by tumors arising from intradermal injection of B16 F1 melanoma cells was also reduced in comparison to controls 7 days after injection. This reduction in angiogenesis correlated with increased levels and activity of circulating matrix metalloproteinase 9 and elevated angiostatin levels in plasma of mutant mice, which reduced endothelial cell proliferation. Ex vivo mutant aortic ring explants developed significantly fewer and thinner aortic sprouts with fewer branch points than controls because of impaired endothelial cell proliferation. In conclusion, the loss of integrins α1β1 and α2β1 in mice results in reduced wound and tumor angiogenesis by cell-autonomous and extrinsic mechanisms.Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.

Vitamin D and vitamin D receptor (VDR) deficiency results in severe symptoms of experimental inflammatory bowel disease in several different models. The intraepithelial lymphocytes of the small intestine contain large numbers of CD8αα(+) T cells that have been shown to suppress the immune response to Ags found there. In this study, we determined the role of the VDR in the development of CD8αα(+) T cells. There are fewer total numbers of TCRαβ(+) T cells in the gut of VDR knockout (KO) mice, and that reduction was largely in the CD8αα(+) TCRαβ(+) cells. Conversely TCRγδ(+) T cells were normal in the VDR KO mice. The thymic precursors of CD8αα(+) TCRαβ(+) cells (triple-positive for CD4, CD8αα, and CD8αβ) were reduced and less mature in VDR KO mice. In addition, VDR KO mice had a higher frequency of the CD8αα(+) TCRαβ(+) precursors (double-negative [DN] TCRαβ(+) T cells) in the gut. The proliferation rates of the DN TCRαβ(+) gut T cells were less in the VDR KO compared with those in wild type. Low proliferation of DN TCRαβ(+) T cells was a result of the very low expression of the IL-15R in this population of cells in the absence of the VDR. Bone marrow transplantation showed that the defect in VDR KO CD8αα(+) TCRαβ(+) cells was cell intrinsic. Decreased maturation and proliferation of CD8αα(+) TCRαβ(+) cells in VDR KO mice results in fewer functional CD8αα(+) TCRαβ(+) T cells, which likely explains the increased inflammation in the gastrointestinal tract of VDR KO and vitamin D-deficient mice.