T cell activation in rheumatoid synovium is B cell dependent

Rheumatoid arthritis results from a T cell-driven inflammation in the synov ial membrane that Is frequently associated with the formation of tertiary l ymphoid structures. The significance of this extranodal lymphoid neogenesis is unknown. Microdissection was used to isolate CD4 T cells residing in sy novial tissue T cell/B cell follicles. CD4 T cells with identical TCR seque nces were represented in independent, nonadjacent follicles, suggesting rec ognition of the same Ag in different germinal centers. When adoptively tran sferred into rheumatoid arthritis synovium-SCID mouse chimeras, these CD4 T cell clones enhanced the production of IFN-gamma, IL-1 beta, and TNF-alpha . In vivo activity of adoptively transferred CD4 T cells required matching of HLA-DRB1 alleles and also the presence of T cell/B cell follicles. HLA-D RB1-matched synovial tissues that were infiltrated by T cells, macrophages, and dendritic cells, but that lacked B cells, did not support the activati on of adoptively transferred CD4 T cell clones, raising the possibility tha t B cells provided a critical function in T cell activation or harbored the relevant Ag. Dependence of T cell activation on B cells was confirmed in B cell depletion studies. Treatment of chimeric mice with anti-CD20 mAb inhi bited the production of IFN-gamma and IL-1 beta, indicating that APCs other than B cells could not substitute in maintaining T cell activation. The ce ntral role of B cells in synovial inflammation identifies them as excellent targets for immunosuppressive therapy.