Transcriptomic Profiling of Human Effector and Regulatory T Cell Subsets Identifies Predictive Population Signatures

After activation, CD4⁺ Th cells differentiate into functionally specialized populations that coordinate distinct immune responses and protect against different types of pathogens. In humans, these effector and memory Th cell subsets can be readily identified in peripheral blood based on their differential expression of chemokine receptors that govern their homeostatic and inflammatory trafficking. Foxp3⁺ regulatory T (Treg) cells can also be divided into subsets that phenotypically mirror each of these effector populations and share expression of key transcription factors and effector cytokines. In this study, we performed comprehensive transcriptional profiling of 11 phenotypically distinct Th and Treg cell subsets sorted from peripheral blood of healthy individuals. Despite their shared phenotypes, we found that mirror Th and Treg subsets were transcriptionally dissimilar and that Treg cell populations showed limited transcriptional diversity compared with Th cells. We identified core transcriptional signatures shared across all Th and Treg cell populations and unique signatures that define each of the Th or Treg populations. Finally, we applied these signatures to bulk Th and Treg RNA-sequencing data and found enrichment of specific Th and Treg cell populations in different human tissues. These results further define the molecular basis for the functional specialization and differentiation of Th and Treg cell populations and provide a new resource for examining Th and Treg specialization in RNA-sequencing data.