Trends in Immunology
Volume 26, Issue 3, March 2005, Pages 150-156
Journal home page for Trends in Immunology

A stromal address code defined by fibroblasts

https://doi.org/10.1016/j.it.2004.11.014Get rights and content

To navigate into and within tissues, leukocytes require guidance cues that enable them to recognize which tissues to enter and which to avoid. Such cues are partly provided at the time of extravasation from blood by an endothelial address code on the luminal surface of the vascular endothelium. Here, we review the evidence that fibroblasts help define an additional stromal address code that directs leukocyte behaviour within tissues. We examine how this stromal code regulates site-specific leukocyte accumulation, differentiation and survival in a variety of physiological stromal niches, and how the aberrant expression of components of this code in the wrong tissue at the wrong time contributes to the persistence of chronic inflammatory diseases.

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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