Continuous Immune Cell Differentiation Inferred From Single-Cell Measurements Following Allogeneic Stem Cell Transplantation

Yang Chen, Tadepally Lakshmikanth, Axel Olin, Jaromir Mikes, Mats Remberger, Petter Brodin

The process of immune system regeneration after allogeneic stem cell transplantation is slow, complex, and insufficiently understood. An entire immune system with all of its cell populations must regenerate from infused donor hematopoietic stem cells over the course of weeks and months post-transplantation. Both innate and adaptive arms of the immune system differ in their capacity and speed to reconstitiute in the recipient, which contributes to inadequacy in global immunity during the delayed reconstitution period. Systems-level analyses of immune systems in human patients have been made possible by high-throughput and high-dimensional, state-of-the-art, single-cell methodologies such as mass cytometry. Mass cytometry has revolutionized our ability to comprehensively profile all immune cell populations simultaneously in blood or tissue samples, providing signatures of differentially regulated cells in a range of clinical conditions. Such kind of systems immunology analyses promise not only for more accurate descriptions of variation between patients but also within individual patients over time, inter-dependencies between cell populations and the inference of developmental trajectories for specific cell populations. Here, we took advantage of a recently performed longitudinal mass cytometry analysis in 26 patients with hematological malignancies followed during the first 12 months following allogeneic stem cell transplantation. We present a proof-of-principle analysis to understand the evolution of individual immune cell populations. By applying non-linear dimensionality reduction and feauture extraction algorithms, we infer trajectories for individual immune cell populations, and map continuous marker expression changes occuring during immune cell regeneration that add novel information about this developmental process.