Copy number variations (CNVs) have been implicated in human diseases. However, it remains unclear how they affect immune dysfunction and autoimmune diseases, including rheumatoid arthritis (RA). Here, we identified a novel LSP1 deletion variant for RA susceptibility located in 11p15.5. We replicated that the copy number of LSP1 is significantly lower in RA patients, which correlates positively with LSP1 protein expression levels. Differentially expressed genes in Lsp1-deficient primary T cells represent cell motility and immune and cytokine responses. Functional assays demonstrated that LSP1, induced by T cell receptor activation, negatively regulates T cell migration by reducing ERK activation in vitro. In mice with T cell-dependent chronic inflammation, loss of Lsp1 promotes migration of T cells into the target tissues as well as draining lymph nodes, exacerbating disease severity. Moreover, RA patients show diminished expression of LSP1 in peripheral T cells with increased migratory capacity, suggesting that the defect in LSP1 signaling lowers the threshold for T cell activation. Our work is the first to demonstrate how CNVs result in immune dysfunction and a disease phenotype. Particularly, our data highlights the importance of LSP1 CNVs and LSP1 insufficiency in the pathogenesis of RA and provides novel insights into the mechanisms underlying T cell migration toward the inflamed synovium in RA. Total RNA was isolated from splenic T cells of Lsp1-deficient and wild-type mice, which were stimulated with anti-CD3/CD28 Abs for 6 hours.