Differential survival of leukocyte subsets mediated by synovial, bone marrow, and skin fibroblasts: Site‐specific versus activation‐dependent survival of T cells and neutrophils

Abstract

Objective. Synovial fibroblasts share a number of phenotype markers with fibroblasts derived from bone marrow. In this study we investigated the role of matched fibroblasts obtained from 3 different sources (bone marrow, synovium, and skin) to test the hypothesis that synovial fibroblasts share similarities with bone marrow-derived fibroblasts in terms of their ability to support survival of T cells and neutrophils.Methods. Matched synovial, bone marrow, and skin fibroblasts were established from 8 different patients with rheumatoid arthritis who were undergoing knee or hip surgery. Resting or activated fibroblasts were cocultured with either CD4 T cells or neutrophils, and the degree of leukocyte survival, apoptosis, and proliferation were measured.Results. Fibroblasts derived from all 3 sites supported increased survival of CD4 T cells, mediated principally by interferon-␤. However, synovial and bone marrow fibroblasts shared an enhanced site-specific ability to maintain CD4 T cell survival in the absence of proliferation, an effect that was independent of fibroblast activation or proliferation but required direct T cell-fibroblast cell contact. In contrast, fibroblastmediated neutrophil survival was less efficient, being independent of the site of origin of the fibroblast but dependent on prior fibroblast activation, and mediated solely by soluble factors, principally granulocytemacrophage colony-stimulating factor.Conclusion. These results suggest an important functional role for fibroblasts in the differential accumulation of leukocyte subsets in a variety of tissue microenvironments. The findings also provide a potential explanation for site-specific differences in the pattern of T cell and neutrophil accumulation observed in chronic inflammatory diseases.Fibroblast-like synoviocytes (FLS) interact with a wide variety of leukocyte subtypes within the synovium. In particular, direct interactions between T cells and FLS have been suggested to contribute to the persistence of synovial inflammation (1). Activated T cells modify fibroblast proliferative capacity and matrix production (2,3), while resting T cells activate FLS in vitro to produce stromelysin, interleukin-6 (IL-6), IL-8, and prostaglandin E 2 (4). A recent study demonstrated that surface-bound IL-15 and intercellular adhesion molecule 1 (ICAM-1) expressed by rheumatoid FLS in vitro induce T cell activation and production of tumor necrosis factor ␣ (TNF␣), interferon-␥ (IFN␥), and IL-17, which, in turn, feed back on FLS to induce IL-6, IL-8, and further IL-15 and ICAM-1 expression (5). A complex paracrine, proinflammatory loop is therefore gen-

T Cells and Stromal Fibroblasts in Human Tumor Microenvironments Represent Potential Therapeutic Targets

“…Fibroblast produced type I interferons, particularly IFN-β, have been shown to rescue activated peripheral blood T lymphocytes from apoptosis when they are deprived of IL-2 common γ chain receptor cytokines (IL-2, IL-4, IL-7, IL-9, IL-15) [110,122]. In our hands, we have been unable to detect IFN-β production by ELISA in the media supernatants of cocultured lung tumor fibroblasts and T lymphocytes.…”

“…For example, skin, bone marrow, and RA synovial fluid fibroblasts all spontaneously make IL-6 [110][111][112]. Increased levels of TNF-α, IL-6, IFN-γ [113] and IL-17A [114] were found when synovial fibroblasts were cultivated with T cells.…”

“…Dermal fibroblasts also increase their level of IL-6 production when cultivated with T cells and this was even more pronounced with allogeneic cultures than when autologous T cells were used [115]. TNF-α, lymphotoxin (TNF-β) [110,116], IFN-γ [117], TGF-β1 [117] and IL-17A [117] represent T lymphocyte-produced cytokines that have been shown to Primary fibroblasts established from the lung tumor of a human cancer patient enhanced the production of IFN-γ by CD3/CD28 antibodyactivated autologous tumor-infiltrating lymphocytes over the level of IFN-γ produced by these T cells when they were activated without fibroblasts present upregulate fibroblast production of IL-6. IL-6 is important in the differentiation of naïve T lymphocytes into T H 17 cells that produce inflammatory IL-17A.…”

Reprogramming of a subpopulation of human blood neutrophils by prolonged exposure to cytokines

“…Neutrophils have, in other respects, a strong capacity to functionally interact with immune cells, fibroblasts, endothelial cells and osteoblasts. [53][54][55][56][57] What would be the functional correlates of this cytokineinduced reprogramming? We show that long-lived neutrophils have diminished migration to certain chemotactic Functions of long-lived neutrophils A Chakravarti et al stimuli, phagocytize more particles and release less of destructive enzymes.…”

Fractalkine mediates T cell–dependent proliferation of synovial fibroblasts in rheumatoid arthritis

“…FLS have also been implicated in regulating the fate of tissue-invasive lymphocytes, placing them in a critical position in the rheumatoid disease process. Specifically, FLS have been described to provide signals to T cells, altering their susceptibility to apoptosis and determining their survival and migration pattern in the inflamed lesions (6)(7)(8). Mutuality in the relationship between FLS and T cells has been suggested by the demonstration that activated T cells determine the functional profile of FLS in a contact-dependent manner (9,10).…”