Src-like adaptor protein (SLAP)-deficiency prevents chronic arthritis in SKG mice (49.7)

Abstract

Abstract Background: Intrinsic defects in lymphocyte signaling have been implicated in the pathogenesis of rheumatoid arthritis (RA) by a mouse model of inflammatory arthritis (SKG). SKG mice have a spontaneous mutation in ZAP-70 that leads to impaired thymocyte development, reduced positive selection and impaired negative selection of thymocytes. These defects result in autoreactive peripheral T cells that cause RA. SLAP is known to influence TCR levels and signaling in developing thymocytes. We hypothesize that SLAP-deficiency can alter TCR avidity and influence the negative selection of SKG autoreactive T cells. Methods: To test this hypothesis we generated SLAP-deficient SKG expressing mice (DSSKO). Results: Thymocytes from DSSKO mice have increased TCR complex mediated signaling as evidenced by increased surface expression of CD5 and ERK phosphorylation. DSSKO mice have a 3-fold increase in thymic and peripheral FOXP3+ Tregs compared to SKG controls. Upon zymosan challenge, none of the DSSKO mice develop chronic arthritis. TH17 cells develop normally in DSSKO and SKG mice treated with zymosan suggesting that arthritis protection was not due to lack of their development. Conclusions: These data support the hypothesis that SLAP deficiency alters thymocyte development possibly by both enhancing the negative selection of autoreactive T cells and converting them to Tregs to prevent the development of arthritis.