The Journal of Experimental Medicine
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Published 20 May 2002. doi:10.1084/jem.20011565
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© Rockefeller University Press, 0022-1007/2002/5/1325/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 10, May 20, 2002 1325-1336
CD8 T Cells Are Required for the Formation of Ectopic Germinal Centers in Rheumatoid Synovitis

Young Mo Kang1, Xiaoyu Zhang1, Ulf G. Wagner1, Hongyu Yang1, Robert D. Beckenbaugh2, Paul J. Kurtin3, Jörg J. Goronzy1 and Cornelia M. Weyand1

1 Departments of Medicine and Immunology, Mayo Clinic, Rochester, MN 55905
2 Department of Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905
3 Department of Pathology, Mayo Clinic, Rochester, MN 55905

Address correspondence to Cornelia M. Weyand, Mayo Clinic, Guggenheim 401, 200 First St. SW, Rochester, MN 55905. Phone: 507-284-1650; Fax: 507-284-5045; E-mail: weyand.cornelia{at}mayo.edu

The assembly of inflammatory lesions in rheumatoid arthritis is highly regulated and typically leads to the formation of lymphoid follicles with germinal center (GC) reactions. We used microdissection of such extranodal follicles to analyze the colonizing T cells. Although the repertoire of follicular T cells was diverse, a subset of T cell receptor (TCR) sequences was detected in multiple independent follicles and not in interfollicular zones, suggesting recognition of a common antigen. Unexpectedly, the majority of shared TCR sequences were from CD8 T cells that were highly enriched in the synovium and present in low numbers in the periphery. To examine their role in extranodal GC reactions, CD8 T cells were depleted in human synovium-SCID mouse chimeras. Depletion of synovial CD8 T cells caused disintegration of the GC-containing follicles. In the absence of CD8 T cells, follicular dendritic cells disappeared, production of lymphotoxin-{alpha}1ß2 markedly decreased, and immunoglobulin (Ig) secretion ceased. Immunohistochemical studies demonstrated that these CD8 T cells accumulated at the edge of the mantle zone. Besides their unique localization, they were characterized by the production of interferon (IFN)-{gamma}, lack of the pore-forming enzyme perforin, and expression of CD40 ligand. Perifollicular IFN-{gamma}+ CD8 T cells were rare in secondary lymphoid tissues but accounted for the majority of IFN-{gamma}+ cells in synovial infiltrates. We propose that CD8+ T cells regulate the structural integrity and functional activity of GCs in ectopic lymphoid follicles.

Key Words: lymphoid follicle • rheumatoid arthritis • lymphoid neogenesis • pathogenesis • CD40


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