This study by Yasumizu et al. provides a comprehensive reference of circulating CD4+ T cell populations in autoimmune diseases, identifying 18 cell types and 12 gene programs. Using single-cell transcriptome analysis, they characterized the cellular heterogeneity of CD4+ T cells and performed a meta-analysis of over 1.8 million peripheral CD4+ T cells from 953 individuals across 20 diseases. The results revealed disease-specific heritability enrichment within the 12 gene programs, offering insights into the role of CD4+ T cells in autoimmune diseases and potential for precision medicine. The study highlights the importance of understanding the complex dynamics of CD4+ T cells in various diseases and the potential of using CD4+ T cell profiles for disease prediction and treatment.This study by Yasumizu et al. provides a comprehensive reference of circulating CD4+ T cell populations in autoimmune diseases, identifying 18 cell types and 12 gene programs. Using single-cell transcriptome analysis, they characterized the cellular heterogeneity of CD4+ T cells and performed a meta-analysis of over 1.8 million peripheral CD4+ T cells from 953 individuals across 20 diseases. The results revealed disease-specific heritability enrichment within the 12 gene programs, offering insights into the role of CD4+ T cells in autoimmune diseases and potential for precision medicine. The study highlights the importance of understanding the complex dynamics of CD4+ T cells in various diseases and the potential of using CD4+ T cell profiles for disease prediction and treatment.