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.