Abstract
A breach of T cell tolerance is considered as a major step in the pathogenesis of rheumatoid arthritis. In collagen-induced arthritis (CIA) model, immunization with type II collagen (COL2) leads to arthritis in mice through T cells responding to the immunodominant COL2(259-273) peptide. T cells could escape from thymus negative selection because endogenous COL2(259-273) peptide only weakly binds to the major histocompatibility complex class II (MHCII) molecule A(q). To investigate the regulation of T cell tolerance, we used a new mouse strain BQ.Col2(266E) with homozygous D266E mutations in the Col2 gene leading to a replacement of the endogenous aspartic acid (D) to glutamic acid (E) at position 266 of the COL2(259-273) peptide, resulting in stronger binding to A(q). We also established BQ.Col2(264R) mice carrying an additional K264R mutation changed the lysine (K) at position 264 to eliminate the major TCR recognition site. The BQ.Col2(266E) mice were fully resistant to CIA, while the BQ.Col2(264R) mice developed severe arthritis. Furthermore, we studied two of the most important non-MHCII genes associated with CIA, i.e., Ncf1 and Fcgr2b. Deficiency of either gene induced arthritis in BQ.Col2(266E) mice, and the downstream effects differ as Ncf1 deficiency reduced Tregs and was likely to decrease expression of autoimmune regulator (AIRE) while Fcgr2b did not. In conclusion, the new human-mimicking mouse model has strong T cell tolerance to COL2, which can be broken by deficiency of Fcgr2b or Ncf1, allowing activation of autoreactive T cells and development of arthritis.