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Rheumatoid fibroblast-like synoviocytes overexpress the chemokine stromal cell-derived factor 1 (CXCL12), which supports distinct patterns and rates of CD4+ and CD8+ T cell migration within synovial tissue.
Arthritis Rheum. 2003 Sep; 48(9):2472-82.AR

Abstract

OBJECTIVE

A characteristic feature of the inflammatory infiltrate in rheumatoid arthritis is the segregation of CD4 and CD8 T lymphocyte subsets into distinct microdomains within the inflamed synovium. The aim of this study was to test the hypothesis that chemokines in general and stromal cell-derived factor 1 (SDF-1; CXCL12) in particular are responsible for generating this distinctive microcompartmentalization.

METHODS

We examined how synovial CD4/CD8 T cell subsets interacted in coculture assays with fibroblasts derived from chronic inflammatory synovial lesions and normal synovial tissue as well as from fetal lung and adult skin. We used the ability of T cells to migrate beneath fibroblasts (a process called pseudoemperipolesis) as an in vitro marker of T cell accumulation within synovial tissue.

RESULTS

Rheumatoid fibroblast-like synoviocytes (FLS) displayed a unique ability to support high levels of CD4 and CD8 T cell pseudoemperipolesis. Nonrheumatoid FLS as well as fetal lung fibroblasts supported low levels of pseudoemperipolesis, while skin-derived fibroblasts were unable to do so. CD8 T cells migrated under fibroblasts more efficiently and at a higher velocity than CD4 T cells, a feature that was intrinsic to CD8 T cells. Rheumatoid fibroblasts constitutively produced high levels of SDF-1 (CXCL12), which was functionally important, since blocking studies showed reductions in T cell pseudoemperipolesis to levels seen in nonrheumatoid FLS. Rheumatoid fibroblasts also constitutively produced high levels of vascular cell adhesion molecule 1 (VCAM-1; CD106), but this did not contribute to T cell pseudoemperipolesis, unlike the case for B cells, which require SDF-1 (CXCL12)-CXCR4 and CD49d-VCAM-1 (CD106) interactions. Importantly, only combinations of rheumatoid FLS and rheumatoid-derived synovial fluid T cells supported pseudoemperipolesis when examined ex vivo, confirming the in vivo relevance of these findings.

CONCLUSION

These studies demonstrate that features intrinsic to both fibroblasts (the production of SDF-1) and CD8/CD4 T cells (the expression of CXCR4) are responsible for the characteristic pattern of T lymphocyte accumulation seen in the rheumatoid synovium. These findings suggest that the SDF-1/CXCR4 ligand/receptor pair is likely to play an important functional role in T lymphocyte accumulation and positioning within the rheumatoid synovium.

Authors+Show Affiliations

Medical Research Council Center for Immune Regulation, University of Birmingham, Birmingham, UK.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

13130466

Citation

Bradfield, Paul F., et al. "Rheumatoid Fibroblast-like Synoviocytes Overexpress the Chemokine Stromal Cell-derived Factor 1 (CXCL12), Which Supports Distinct Patterns and Rates of CD4+ and CD8+ T Cell Migration Within Synovial Tissue." Arthritis and Rheumatism, vol. 48, no. 9, 2003, pp. 2472-82.
Bradfield PF, Amft N, Vernon-Wilson E, et al. Rheumatoid fibroblast-like synoviocytes overexpress the chemokine stromal cell-derived factor 1 (CXCL12), which supports distinct patterns and rates of CD4+ and CD8+ T cell migration within synovial tissue. Arthritis Rheum. 2003;48(9):2472-82.
Bradfield, P. F., Amft, N., Vernon-Wilson, E., Exley, A. E., Parsonage, G., Rainger, G. E., Nash, G. B., Thomas, A. M., Simmons, D. L., Salmon, M., & Buckley, C. D. (2003). Rheumatoid fibroblast-like synoviocytes overexpress the chemokine stromal cell-derived factor 1 (CXCL12), which supports distinct patterns and rates of CD4+ and CD8+ T cell migration within synovial tissue. Arthritis and Rheumatism, 48(9), 2472-82.
Bradfield PF, et al. Rheumatoid Fibroblast-like Synoviocytes Overexpress the Chemokine Stromal Cell-derived Factor 1 (CXCL12), Which Supports Distinct Patterns and Rates of CD4+ and CD8+ T Cell Migration Within Synovial Tissue. Arthritis Rheum. 2003;48(9):2472-82. PubMed PMID: 13130466.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Rheumatoid fibroblast-like synoviocytes overexpress the chemokine stromal cell-derived factor 1 (CXCL12), which supports distinct patterns and rates of CD4+ and CD8+ T cell migration within synovial tissue. AU - Bradfield,Paul F, AU - Amft,Nicole, AU - Vernon-Wilson,Elizabeth, AU - Exley,Andrew E, AU - Parsonage,Greg, AU - Rainger,G Ed, AU - Nash,Gerard B, AU - Thomas,Andrew M C, AU - Simmons,David L, AU - Salmon,Mike, AU - Buckley,Christopher D, PY - 2003/9/18/pubmed PY - 2003/10/18/medline PY - 2003/9/18/entrez SP - 2472 EP - 82 JF - Arthritis and rheumatism JO - Arthritis Rheum VL - 48 IS - 9 N2 - OBJECTIVE: A characteristic feature of the inflammatory infiltrate in rheumatoid arthritis is the segregation of CD4 and CD8 T lymphocyte subsets into distinct microdomains within the inflamed synovium. The aim of this study was to test the hypothesis that chemokines in general and stromal cell-derived factor 1 (SDF-1; CXCL12) in particular are responsible for generating this distinctive microcompartmentalization. METHODS: We examined how synovial CD4/CD8 T cell subsets interacted in coculture assays with fibroblasts derived from chronic inflammatory synovial lesions and normal synovial tissue as well as from fetal lung and adult skin. We used the ability of T cells to migrate beneath fibroblasts (a process called pseudoemperipolesis) as an in vitro marker of T cell accumulation within synovial tissue. RESULTS: Rheumatoid fibroblast-like synoviocytes (FLS) displayed a unique ability to support high levels of CD4 and CD8 T cell pseudoemperipolesis. Nonrheumatoid FLS as well as fetal lung fibroblasts supported low levels of pseudoemperipolesis, while skin-derived fibroblasts were unable to do so. CD8 T cells migrated under fibroblasts more efficiently and at a higher velocity than CD4 T cells, a feature that was intrinsic to CD8 T cells. Rheumatoid fibroblasts constitutively produced high levels of SDF-1 (CXCL12), which was functionally important, since blocking studies showed reductions in T cell pseudoemperipolesis to levels seen in nonrheumatoid FLS. Rheumatoid fibroblasts also constitutively produced high levels of vascular cell adhesion molecule 1 (VCAM-1; CD106), but this did not contribute to T cell pseudoemperipolesis, unlike the case for B cells, which require SDF-1 (CXCL12)-CXCR4 and CD49d-VCAM-1 (CD106) interactions. Importantly, only combinations of rheumatoid FLS and rheumatoid-derived synovial fluid T cells supported pseudoemperipolesis when examined ex vivo, confirming the in vivo relevance of these findings. CONCLUSION: These studies demonstrate that features intrinsic to both fibroblasts (the production of SDF-1) and CD8/CD4 T cells (the expression of CXCR4) are responsible for the characteristic pattern of T lymphocyte accumulation seen in the rheumatoid synovium. These findings suggest that the SDF-1/CXCR4 ligand/receptor pair is likely to play an important functional role in T lymphocyte accumulation and positioning within the rheumatoid synovium. SN - 0004-3591 UR - https://www.unboundmedicine.com/medline/citation/13130466/Rheumatoid_fibroblast_like_synoviocytes_overexpress_the_chemokine_stromal_cell_derived_factor_1__CXCL12__which_supports_distinct_patterns_and_rates_of_CD4+_and_CD8+_T_cell_migration_within_synovial_tissue_ L2 - https://doi.org/10.1002/art.11219 DB - PRIME DP - Unbound Medicine ER -