N. Mehrotra, D. Bangs, A. L. Figueroa, G. C. W. Bee, R. Lai, T. Shinkawa, K. C. Osum, A. Freuchet, Z. Zhang, L. Nogueira, T. Heim, K. Cadwell, M. Starnbach, S. Behar, S. Spranger, M. Pepper, M. K. Jenkins, J. Merkenschlager, C. Benoist, D. Zemmour, the immgenT Project
CD4+ T cells are orchestrators of the immune system with diverse effector functions. Their full molecular diversity remains unclear due to the lack of a unified framework. Within the immgenT project, we profiled RNA, surface markers, and TCR clonotypes in conventional CD4+ T cells across >700 samples. Integration with a joint RNA-protein deep generative model revealed an ensemble of 20 CD4 states that account for all cells across tissues and challenges. Small, highly polarized clusters ("tips") that evoke Th1, Th2, Th17, and Tfh states co-exist with a majority of activated cells with mixed programs occupying "midland" states. Unlike CD8+ T cells, memory CD4+ cells largely mapped to the same states as effectors. Resting states proved quite diverse, and we uncovered unexpected similarities between Tfh and chronically stimulated states. Together, immgenT provides a unified molecular reference for CD4+ T cell diversity.