Significance We screened rheumatoid arthritis (RA)-associated copy number variations (CNVs) across the whole genome and identified significant deletion variants encompassing leukocyte-specific protein 1 (LSP1) gene. Functional assays revealed that LSP1, induced by T-cell receptor activation, negatively regulates T-cell migration. Loss of Lsp1 promotes T-cell migration into antigen-instilled tissues and draining lymph nodes in mice with T-cell–dependent chronic inflammation. Moreover, patients with RA show diminished expression of LSP1 in peripheral T cells with increased migratory capacity. To our knowledge, our work is the first to demonstrate how CNVs result in immune dysfunction and a disease phenotype, highlighting the importance of LSP1 CNVs and LSP1 insufficiency in the pathogenesis of RA.