Antigen persistence in cancer and chronic infections profoundly alters T cell differentiation and function, leading antigen-specific cells into a collection of transcriptional and epigenetic states commonly referred to as “exhausted” 1. Occasionally, however, malignant cells and pathogens escape immune control, leading to cancer and chronic infections. In response to malignant cells and pathogens, mammals (and presumably most jawed vertebrates) mount an adaptive immune response characterized by a finely-tuned balance of several specialized T cell subtypes with distinct migratory and functional properties and metabolic lifestyles. A meta-analysis of tumor-infiltrating T cells from several cohorts reveals a strong conservation of T cell subtypes between human and mouse, providing a consistent basis to describe T cell heterogeneity across studies, diseases, and species. ProjecTILs accurately predicts the effects of cell perturbations and identifies gene programs that are altered in different conditions and tissues. In contrast to other methods, ProjecTILs allows not only accurate embedding of new scRNA-seq data into a reference without altering its structure, but also characterizing previously unknown cell states that “deviate” from the reference. ![]() Here we generate reference T cell atlases for cancer and viral infection by multi-study integration, and develop ProjecTILs, an algorithm for reference atlas projection. ![]() However, consistent definition of cell subtypes and cell states across studies and diseases remains a major challenge. Single-cell RNA sequencing (scRNA-seq) has revealed an unprecedented degree of immune cell diversity.
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