Evidence for the continuous recruitment and activation of T cells into the joints of patients with rheumatoid arthritis.
Rheumatoid arthritis (RA) synovial fluid (SF) T cells express the activation markers CD69, HLA-DR and very late antigen (VLA)-1, but surprisingly few bear interleukin-2 receptors (CD25). This unusual activation state is commonly assumed to be due to stimulation by local antigen, yet T cells activated in vitro express activation antigens in the clearly defined sequence: CD69, CD25, HLA-DR and finally VLA-1. Two possible explanations for the activation state of SF cells are: first, they comprise several subpopulations each expressing different activation antigens or, second, activation markers are up-regulated by mechanisms other than antigen stimulation. To examine these hypotheses, double- and triple-color immunofluorescence techniques were applied to four T cell populations: normal peripheral blood T cells activated in vitro, RA SF T cells, T cells from an in vivo model of migration [tuberculin purified protein derivative (PPD)-induced skin blisters] and T cells co-cultured with endothelial cells (EC). The results confirmed that in vitro activated T cells expressed activation markers in the sequence described above, with significant CD25 expression and few cells co-expressing CD69 with HLA-DR or VLA-1. In contrast, almost half the SF T cells were CD69+HLA-DR+ but CD25-; a significant minority were CD69+VLA-1+. T cells from PPD-induced skin blisters were already HLA-DR+ and VLA-1+ at 24 h, although, in vitro, PPD-activated T cells up-regulated HLA-DR and VLA-1 only after 1 week, suggesting that pre-activated T cells were preferentially recruited into the blisters. Finally, T cells were found to up-regulate CD69 and, to a lesser extent, HLA-DR after adhering to EC in vitro. In summary, the paradoxical activation state of SF T cells cannot be explained solely by single or multiple rounds of activation in situ. At least two other mechanisms, the preferential recruitment of pre-activated T cells and the induction of HLA-DR and especially CD69 by endothelial contact during migration, may also play a role.
Rheumatology Unit, United Medical School of Guy's Hospital, London.
F
F
Iannone
V M
VM
Corrigall
G H
GH
Kingsley
G S
GS
Panayi
D000328:Adult; D015703:Antigens, CD / Q000032:analysis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000032:analysis; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000166:cytology / Q000502:physiology; D005260:Female; D006684:HLA-DR Antigens / Q000032:analysis; D006801:Humans; D037181:Lectins, C-Type; D017493:Leukocyte Common Antigens / Q000032:analysis; D008213:Lymphocyte Activation; D008297:Male; D013582:Synovial Fluid / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014373:Tuberculin / Q000276:immunology; D000099192:CD69 Antigens
D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D018106:CD28 Antigens; D017252:CD3 Complex; D006684:HLA-DR Antigens; D037181:Lectins, C-Type; D017493:Leukocyte Common Antigens; D014373:Tuberculin; D000099192:CD69 Antigens