Role of Mls-1 locus and clonal deletion of T cells in susceptibility to collagen-induced arthritis in mice

The role of T cell-mediated and humoral immunity to type II collagen has been well documented in collagen-induced arthritis (CIA). Previous work from our laboratory has indicated that genomic deletions of TCR V(β) genes may play a role in CIA resistance in mice. This indicated a selectivity of TCR usage by autoreactive T cells in CIA in mice. Certain strains of mice, although having a normal genomic V(β) TCR repertoire, can show clonal deletion of peripheral T cells that bear specific V(β) gene products in their TCR. These clonally deleted T cells are reactive with self-Ag such as minor lymphocyte stimulation (Mls) Ag. An Mls-congenic strain, BALB.D2.Mls^a, which differs only at the Mls-1^a locus from BALB/c (Mls-1^b), was used to examine the effect of clonal deletion of Mls-1^a-reactive T cells in CIA. These two strains were crossed to three CIA-susceptible strains, B10.RIII (H-2(r), Mls-1^b), DBA/1 (H-2(q), Mls-1^a), and B10.Q (H-2(q), Mls-1^b), and the crosses were injected with type II collagen. A significantly decreased incidence of arthritis was observed in the (BALB.D2.Mls^a x B10.Q)F₁ hybrids, compared with (BALB/c x B10.Q)F₁ hybrids, upon immunization with chick type II collagen. The BALB.D2.Mls^a cross mice also had significantly lower levels of anti-mouse collagen antibodies. Flow cytometric analysis confirmed the clonal deletion of Mls-1^a-reactive V(β)8.1, V(β)6, V(β)7, and V(β)9 subsets in the (BALB.D2.Mls^a x B10.Q)F₁ hybrids. The study of H-2(q/d) mice in (BALB.D2.Mls^a x B10.Q) x B10.Q backcrosses demonstrated a significant correlation between CIA resistance and Mls-1^a locus. On the other hand, B10.RIII crosses showed only a modest decrease in CIA incidence in the presence of Mls-1^a. As expected, all the DBA/1 crosses had an equal incidence of CIA, which was somewhat less than that seen in DBA/1 mice themselves. These studies point out that the Mls-1^a locus could play a role in decreasing CIA incidence by clonal deletion of T cells bearing specific V(β) TCR, which may be involved in the pathogenesis of CIA. The influence of the clonal deletion of T cells on CIA, and hence the usage of specific V(β) TCR by autoreactive anti-type II collagen T cells, however, depends not only on the source of the type II collagen and the MHC class II molecules involved but also on other background genes in mice.