Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by excessive activation of T and B lymphocytes and breakdown of immune tolerance to autoantigens. Despite several mechanisms including the genetic alterations and inflammatory responses have been reported, the overall signature genes in CD4⁺ T cells and how they affect the pathological process of SLE remain to be elucidated. This study aimed to identify the crucial genes, potential biological processes and pathways underlying SLE pathogenesis by integrated bioinformatics. The gene expression profiles of isolated peripheral CD4⁺ T cells from SLE patients with different disease activity and healthy controls (GSE97263) were analyzed, and 14 co-expression modules were identified using weighted gene co-expression network analysis (WGCNA). Some of these modules showed significantly positive or negative correlations with SLE disease activity, and primarily enriched in the regulation of type I interferon and immune responses. Next, combining time course sequencing (TCseq) with differentially expressed gene (DEG) analysis, crucial genes in lupus CD4⁺ T cells were revealed, including some interferon signature genes (ISGs). Among these genes, we identified 4 upregulated genes (PLSCR1, IFI35, BATF2 and CLDN5) and 2 downregulated genes (GDF7 and DERL3) as newfound key genes. The elevated genes showed close relationship with the SLE disease activity. In general, our study identified 6 novel biomarkers in CD4⁺ T cells that might contribute to the diagnosis and treatment of SLE.