ABSTRACT
CD248 is a cell surface receptor that specifically identifies fibroblasts and pericytes during development and in association with cancer and inflammation. However, its function is poorly defined and its role in lymphoid organs not studied. Here, we used (4-hydroxy-3-nitrophenyl)acetyl chicken gamma-globulin immunisation and mice lacking CD248 to study whether CD248 modulates popliteal LN (pLN) expansion and subsequent immune responses. We have found that CD248 is required for complete pLN expansion but not for co-ordination of B and T cell compartmentalisation or antibody production following (4-hydroxy-3-nitrophenyl)acetyl chicken gamma-globulin immunisation. In vitro, we show that CD248 expression in human MG63 stromal cells and mouse embryonic fibroblasts leads to a pro-proliferative and pro-migratory phenotype. This correlates with a proliferating CD248(+) population observed in vivo during pLN expansion. Taken together, these data highlight a role for CD248 in secondary lymphoid organ remodelling during adaptive immune responses.
Subject(s)
Antigens, CD/metabolism , Antigens, Neoplasm/metabolism , Fibroblasts/metabolism , Lymph Nodes/immunology , Neoplasm Proteins/metabolism , Pericytes/metabolism , Stromal Cells/metabolism , Animals , Antibody Formation/genetics , Antigens, CD/genetics , Antigens, CD/immunology , Antigens, Neoplasm/immunology , B-Lymphocytes/immunology , Biomarkers/metabolism , Cell Communication/genetics , Cell Line , Cell Movement/genetics , Cell Proliferation , Chickens , Fibroblasts/immunology , Fibroblasts/pathology , Haptens/immunology , Humans , Immunization , Lymph Nodes/growth & development , Lymph Nodes/pathology , Mice , Mice, Knockout , Neoplasm Proteins/genetics , Neoplasm Proteins/immunology , Nitrophenols/immunology , Pericytes/immunology , Pericytes/pathology , Phenylacetates/immunology , Stromal Cells/immunology , Stromal Cells/pathology , T-Lymphocytes/immunology , gamma-Globulins/immunologyABSTRACT
According to the prevailing paradigm, neutrophils are short-lived cells that undergo spontaneous apoptosis within 24 hours of their release from the bone marrow. However, neutrophil survival can be significantly prolonged within inflamed tissue by cytokines, inflammatory mediators, and hypoxia. During screening experiments aimed at identifying the effect of the adhesive microenvironment on neutrophil survival, we found that VCAM-1 (CD106) was able to delay both spontaneous and Fas-induced apoptosis. VCAM-1-mediated survival was as efficient as that induced by the cytokine IFN-beta and provided an additive, increased delay in apoptosis when given in combination with IFN-beta. VCAM-1 delivered its antiapoptotic effect through binding the integrin alpha9beta1. The alpha9beta1 signaling pathway shares significant features with the IFN-beta survival signaling pathway, requiring PI3 kinase, NF-kappaB activation, as well as de novo protein synthesis, but the kinetics of NF-kappaB activation by VCAM-1 were slower and more sustained compared with IFN-beta. This study demonstrates a novel functional role for alpha9beta1 in neutrophil biology and suggests that adhesive signaling pathways provide an important extrinsic checkpoint for the resolution of inflammatory responses in tissues.
