CD4 and CD8 T cells in susceptibility/protection to collagen-induced arthritis in HLA-DQ8-transgenic mice: implications for rheumatoid arthritis.
To investigate the role of CD4 and CD8 T cells in arthritis, we generated transgenic mice deficient in CD4 and CD8 molecules expressing RA-susceptible gene HLA-DQ8. DQ8.CD4(-/-) mice were resistant to developing collagen-induced arthritis (CIA). However, DQ8.CD8(-/-) mice developed CIA with increased incidence and more severity than DQ8 mice. Both DQ8.CD8(-/-) and DQ8 mice produced rheumatoid factor. In addition, DQ8.CD8(-/-) mice produced antinuclear Abs. The B cell compartment and expression of DQ8 were normal in all the strains, although frequency of cells expressing DQ8 was less in CD4(-/-) mice. An increased frequency of CD3(+) double-negative (DN) T cells was found in DQ8.CD8(-/-) compared with DQ8.CD4(-/-) and DQ8 mice. These CD3(+) DN T cells produced high amounts of IL-10 in CD8-deficient mice. Analysis of cell division using a cell cycle tracking dye showed a higher rate of division of CD3(+) and CD3(+) DN T cells in DQ8.CD8(-/-) mice compared with DQ8.CD4(-/-) and DQ8 mice. Decreased apoptosis was seen in CIA-susceptible DQ8 and CD8-deficient mice, indicating a defect in activation-induced cell death. These observations suggest that CD4 cells are necessary for initiation of CIA in DQ8 mice. We hypothesize that CD8(+) T cells are not capable of initiating CIA in DQ8-transgenic mice but may have a regulatory/protective effect.
Taneja
Veena
V
Department of Immunology and Division of Rheumatology, Mayo Clinic, Rochester, MN 55905, USA. taneja.veena@mayo.edu
Taneja
Neelam
N
Paisansinsup
Tawatchai
T
Behrens
Marshall
M
Griffiths
Marie
M
Luthra
Harvinder
H
David
Chella S
CS
D000818:Animals; D000974:Antibodies, Antinuclear / Q000032:analysis; D001172:Arthritis, Rheumatoid / Q000209:etiology* / Q000517:prevention & control; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D003094:Collagen / Q000276:immunology*; D004198:Disease Susceptibility; D005260:Female; D006683:HLA-DQ Antigens / Q000502:physiology*; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D012217:Rheumatoid Factor / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D000974:Antibodies, Antinuclear; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D003094:Collagen; D012217:Rheumatoid Factor