Conversion in vivo from an early dominant Th0/Th1 response to a Th2 phenotype during the development of collagen-induced arthritis.
Over the past decade, the central role of T cells in the process of collagen-induced arthritis (CIA) has been extensively documented. The inflammatory features of CIA and its successful modulation after treatment in vivo with Th2 lymphokines, known to down-regulate proinflammatory cytokines, classify CIA as a Th1-mediated disease. However, no direct evidence for the presence of the different T helper subsets has been obtained. To identify the collagen-specific CD4+ T cell subset(s) developing during the course of CIA, lymph nodes from susceptible DBA/1 mice (H-2q) were harvested at different times after injection of bovine type II collagen in Freund's complete adjuvant and checked by enzyme-linked immunospot assay for the production of interferon (IFN)-gamma and interleukin (IL)-4. The results clearly showed that type II collagen-specific T cells secreting either IFN-gamma, IL-4, or both, develop early in vivo, before the onset of arthritis: the number of IFN-gamma-secreting cells was already maximal 15 days after immunization, whereas more IL-4-secreting cells were found at day 30, just before the onset of clinical arthritis. Another strategy was to establish collagen-specific CD4+ T cell lines and sublines in vitro and to analyze their lymphokine secretion pattern. Lines generated 8 days after immunization displayed a mixed lymphokine secretion pattern characteristic of Th0 cells or of a mixture of Th1 and Th2 cells. After limiting dilution of a day 8 line, 60% of the growing sublines were Th0-like (secreting IFN-gamma, IL-4, and IL-5), and 25% were Th1 (secreting IFN-gamma). By day 25 post-immunization, 33% of the generated sublines were Th0-like, 11% Th1, and 56% Th2 (secreting IL-4 and IL-5). Moreover, all the sublines raised from the lymph nodes of arthritic mice harvested at day 55 secreted high amounts of Th2 lymphokines, and only 3 out of 14 also produced some IFN-gamma. This study demonstrates that during the course of CIA the collagen-specific CD4+ T cell response shifts in vivo from a dominant Th0/Th1 response to a clear Th2 phenotype. These results contribute to our understanding of the collagen-specific CD4+ T helper subsets which develop during the induction and clinical phases of CIA.
Doncarli
A
A
INSERM U 283, Université Descartes, Paris, France.
Stasiuk
L M
LM
Fournier
C
C
Abehsira-Amar
O
O
D000818:Animals; D001169:Arthritis, Experimental / Q000209:etiology / Q000276:immunology* / Q000378:metabolism; D002417:Cattle; D003094:Collagen / Q000008:administration & dosage / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D005620:Freund's Adjuvant; D007114:Immunization; D016130:Immunophenotyping; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D008198:Lymph Nodes / Q000166:cytology / Q000378:metabolism; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D018417:Th1 Cells / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology* / Q000378:metabolism
D000939:Epitopes; D015847:Interleukin-4; D007371:Interferon-gamma; D003094:Collagen; D005620:Freund's Adjuvant