T cells from systemic lupus erythematosus (SLE) patients exhibit a hyperactive phenotype with defects in homeostasis, signaling and cytokine production. We previously uncovered new roles for serine arginine-rich splicing factor 1 (SRSF1) in the control of genes involved in signaling and cytokine production in T cells. SRSF1 expression is decreased in T cells from patients with SLE and low SRSF1 levels are associated with severe disease activity. Mice with a T cell-conditional deficiency of Srsf1 exhibit T cell hyperactivity, systemic autoimmunity, and lupus-like nephritis. However, little is known about the molecular targets controlled by SRSF1 and whether they are implicated in human SLE. Our goal was to identify the molecular signatures controlled by SRSF1 and evaluation by comparative bioinformatic analysis if these genes and pathways are dysregulated in SLE. We curated publicly available gene array datasets from SLE patients and compared them with SRSF1-regulated genes in CD4 T cells from Srsf1-deficient mice. We identified 169 overlapping genes controlled by SRSF1 that are aberrantly expressed in T cells of SLE patients. Pathway analysis revealed genes enriched in interferon signaling, cytokine production, cytokine receptor interaction, cell migration and lysosomal clearance pathways. Our data reveal that SRSF1 controls genes involved in T cell homeostasis, activation, cytokine regulation/signaling and differentiation, which are altered in patients with SLE. Therefore, SRSF1 is an important regulator of T cell function and its deficiency may lead to a hyperactive T cell phenotype in SLE patients. Targeting SRSF1 and the genes controlled by this molecule to correct the aberrant T