Quantifying Adaptive Evolution of the Human Immune Cell Landscape

The human immune system is under relentless evolutionary pressure due to its critical role as the first line of defense against pathogens. While previous studies have highlighted the high adaptive evolution rate of immune-related protein-coding genes, these analyses often neglect the cellular context, leaving the adaptive significance of specific immune cell types and states largely unexplored. Leveraging data from the Human Cell Atlas, we examined the adaptation rates of protein-coding genes across the human immune landscape at cellular resolution. Our findings reveal that both progenitor cells during development and adult immune cells in barrier tissues exhibit markedly elevated rates of adaptation. Notably, tissue-resident T cells and NK cells in the adult lung—situated in compartments exposed to respiratory pathogens— demonstrate clear evidence of positive selection. Furthermore, analysis of iPSC-derived macrophages responding to diverse challenges, such as cytokines and microbial infections, underscores the adaptive importance of early immune responses in controlling pathogen proliferation and spread. These observations suggest that evolutionary pressures have shaped immune cell populations to provide host advantages at critical stages of infection. Together, our study uncovers spatio-temporal and functional biases in immune adaptation, offering insights into the evolutionary forces that have sculpted the complexity, architecture, and functionality of the human immune system.