Abstract 1104: CD8 T Cells Regulate Angiogenesis in Rheumatoid Arthritis by Suppressing the Production of Angio-inhibitor Thrombospondin-2 (TSP2)
Y. Park, Y. Kang, H. Sawai, J. Goronzy, C. Weyand

Objective: New blood vessel formation (angiogenesis) is a feature of rheumatoid synovium. This study explored whether CD8 T cells influence the synovial scaffold by regulating the formation of new blood vessels.

Methods: Rheumatoid synovium-SCID mouse chimeras were treated with anti-CD8 antibodies or control IgG. In other experiments, synovial CD8 T cells were cloned, expanded and adoptively transferred into synovium-SCID chimeras. Inflammatory activity was quantified through real-time PCR of IFN-gand TNF-amRNA. Angiogenesis was evaluated by staining for CD146+ endothelial cells and by quantifying the expression of the angio-inhibitory protein thrombospondin-2 (TSP2) by immunohistochemistry, Western blotting and real-time PCR.

Results: Antibody-mediated depletion of CD8 T cells from synovium engrafted into SCID mice resulted in:

1. a profound reduction of microvessels; both vessel density and total vessel area decreased significantly (P<0.001);
2. decreased transcription of IFN-g(P<0.005) and TNF-a(P<0.001);
3. increased production of the anti-angiogenic mediator TSP2 (P <0.001).

Adoptively transferred CD8 T cell clones enhanced IFN-? and TNF-abut suppressed the deposition of TSP2 in the synovial lesions of SCID chimeras engrafted with either syngeneic or HLA class I matched heterologous tissue. Fibroblast-like synoviocytes (FLS) were identified as the major source for TSP2 in the synovium. Interaction of CD8 T cell lines, generated to specifically recognize FLS, with cultured synovial fibroblasts resulted in induction of IFN-gand TNF-aand suppression of TSP2. TSP2 downregulation could be mimicked by culturing FLS with IFN-gor TNF-a, indicating that CD8 T cells function through cytokine release.

Conclusions: CD8 T cells regulate the functional activity of synoviocytes, including their role in controlling neoangiogenesis in synovitis. By suppressing the production of the angio-inhibitory protein TSP2, tissue-invading CD8 T cells overrule the ability of synoviocytes to protect the synovial microenvironment from lymphoid neogenesis and new blood vessel formation.

Editorial Comment: This is an interesting and novel finding linking basic immune cell functions with synovial cell function and angiogenesis. It is tantalizing to consider whether local enhancement of expression of TSP2 (e.g., through gene delivery) could reduce the bulk of rheumatoid synovium via downregulation of blood supply.

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