A comprehensive single-cell transcriptome analysis of circulating CD4⁺ T cells in autoimmune diseases was conducted, involving 20 diseases, 953 individuals, and 1.8 million cells. The study identified 18 cell types and 12 gene programs in blood CD4⁺ T cells, revealing disease-specific cellular characteristics through integration of genome-wide association studies and single-cell meta-analysis. The results showed that the 12 transcriptional programs were useful in characterizing each autoimmune disease and predicting its clinical status. Additionally, genetic variants associated with autoimmune diseases showed disease-specific enrichment within the 12 gene programs. The study provided insights into the role of CD4⁺ T cells in autoimmune diseases and their potential for precision medicine. The analysis also revealed that CD4⁺ T cell alterations varied across different autoimmune diseases, with some diseases showing specific changes in Treg cells and Th17 cells. The study also highlighted the importance of CD4⁺ T cell features in predicting disease status, with models based on CD4⁺ T cell profiles achieving high accuracy in predicting autoimmune diseases. The study also identified disease-specific heritability enrichment in CD4⁺ T cell gene programs, suggesting that genetic factors play a significant role in autoimmune diseases. Overall, the study provided a detailed landscape of CD4⁺ T cell populations in autoimmune diseases, offering new insights into the mechanisms underlying these conditions and their potential for targeted therapies.A comprehensive single-cell transcriptome analysis of circulating CD4⁺ T cells in autoimmune diseases was conducted, involving 20 diseases, 953 individuals, and 1.8 million cells. The study identified 18 cell types and 12 gene programs in blood CD4⁺ T cells, revealing disease-specific cellular characteristics through integration of genome-wide association studies and single-cell meta-analysis. The results showed that the 12 transcriptional programs were useful in characterizing each autoimmune disease and predicting its clinical status. Additionally, genetic variants associated with autoimmune diseases showed disease-specific enrichment within the 12 gene programs. The study provided insights into the role of CD4⁺ T cells in autoimmune diseases and their potential for precision medicine. The analysis also revealed that CD4⁺ T cell alterations varied across different autoimmune diseases, with some diseases showing specific changes in Treg cells and Th17 cells. The study also highlighted the importance of CD4⁺ T cell features in predicting disease status, with models based on CD4⁺ T cell profiles achieving high accuracy in predicting autoimmune diseases. The study also identified disease-specific heritability enrichment in CD4⁺ T cell gene programs, suggesting that genetic factors play a significant role in autoimmune diseases. Overall, the study provided a detailed landscape of CD4⁺ T cell populations in autoimmune diseases, offering new insights into the mechanisms underlying these conditions and their potential for targeted therapies.