Trends in Immunology
A stromal address code defined by fibroblasts
Section snippets
Vascular address codes
Naïve lymphocytes continuously cycle through the vascular and lymphatic circulation until they encounter their cognate antigen, displayed by professional antigen-presenting cells, in lymph nodes. They gain entry to lymph nodes because they express the correct address code: high levels of L-selectin and the chemokine receptor CCR7 2, 3, 4, 5. These molecules recognize ligands, which are found on the lumenal side of lymph node high endothelial venules (HEVs). CCR7 engagement causes cells to
Dendritic cells (DCs) communicate tissue identity to T cells
There is now good evidence to suggest that T cells are imprinted with an endothelial address code as they undergo activation in the lymph node, and that a cognate interaction with interdigitating DCs is sufficient for this process (reviewed in Ref. [9]).
DCs isolated from various lymphoid organs all share the ability to activate CD8+ T cells but only those taken from Peyer's patches (PPs) imprint them with the gut-homing code (α4β7, CCR9+) [10]. The positional identity of DCs appears stable
Address codes are sequentially encountered
Leukocytes arriving in interstitial tissue exhibit different properties to their blood-borne counterparts. In particular, their ability to respond to stromally derived cues for proliferation, differentiation, positioning and survival is likely to be radically altered [14]. Despite the inherently sequential nature of leukocyte trafficking, the effects of transendothelial migration on leukocyte behaviour within tissues remain poorly characterized.
For obvious experimental and technical reasons, in
Fibroblast diversity, autonomy and positional identity
Fibroblasts isolated from different tissues display different functional properties (reviewed in Ref. [21]). Consistent with the varying biophysical requirements of different tissues, phenotypic differences in the well-known structural functions of fibroblasts, such as migratory capacity, extra cellular matrix (ECM) production and degradation and contractility, have been reported. The less well-known immunomodulatory functions of fibroblasts are also known to vary according to anatomical site
Stromal address codes in leukocyte development
Fibroblast-like stromal cells are required to support effective haematopoiesis and help define the bone marrow stromal niche [30]. Recent work has revealed that the expression of a few crucial molecules can support leukocyte survival, regulate leukocyte position and control leukocyte differentiation in a variety of stem-cell niches, including the bone marrow, thymus and lymph node. These molecules appear to constitute part of a stromal address code that consists of a homeostatic or constitutive
Pathological stromal codes
An increasing number of studies suggest a key pathological role for the ectopic temporal and spatial expression of cytokines and chemokines in diseases, such as rheumatoid arthritis (RA), autoimmune liver disease, thyroid disease and diabetes 48, 49, 50. These chronic immune-mediated inflammatory conditions are characterized by the abnormal persistence and continued episodic recruitment of infiltrating inflammatory cells, which is accompanied by a local expansion and activation of fibroblasts
Origins of fibroblasts: mesenchymal proliferation, local transdifferentiation from epithelium or seeding from bone marrow?
Despite increasing evidence for their crucial immunomodulatory functions, fibroblasts are still widely thought of as primary mesenchymal cells that are deposited in tissue interstitia, simply as a consequence of organ development. It is not disputed that their developmental origin is the primary mesenchyme, and that fibroblasts can proliferate to generate new fibroblasts, however, emerging evidence suggests that immature fibroblasts are not phenotypically equivalent to primary mesenchyme. This
Concluding remarks
The prevailing paradigm accounting for the accumulation of specific leukocyte subsets in an inflamed tissue is based on endothelial selectivity at the point of recruitment. However, this ignores the role of selective retention within the tissue, mediated by a stromal address code that is defined, at least in part, by fibroblasts. A combinatorial stromal address code involving homeostatic or constitutive chemokines (CXCL12, CXCL13, CCL19, CCL21), adhesion molecules (VCAM-1) and cytokines (IL-6
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