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Stankiewicz, Laura

University of British Columbia

T cells play a critical role in adaptive immunity by recognizing self, versus non-self antigens, effectively protecting against pathogens and damaged or cancerous body cells. The application of T cells in cellular medicine to treat cancer and immunological disorders, as well as in personalized medicine to model disease pathologies, is rapidly expanding due to the potent role of T cells as mediators of the adaptive immune response. Pluripotent stem cell-derived T (PSC-T) cells have the potential to expand access to immunotherapies and disease modeling. However, current in vitro technologies have failed to recapitulate the signaling environments necessary to guide PSC-T cells towards mature helper and cytotoxic T cells in defined, feeder-free culture systems. T cells develop in the thymus, an organ specialized to support stage-specific T cell training via organization into spatially-defined niches. Previously, understanding of human T cell development and thymus niche biology was limited to interpretations from experimental animal models and observational learnings from patient populations with genetic mutations. These interpretations have proven challenging to adapt for in vitro PSC-T cell culture technology development. Here, we employ closed-loop learning to probe human T cell development. We first apply spatial multiomic technologies to create a spatially-defined map of tissue niches guiding T cell development in human postnatal thymus. We then test key insights into thymus niche biology in vitro using our PSC-T cell differentiation platform, demonstrating how our in vivo reference can be applied in vitro to guide T-lineage branching towards mature helper and cytotoxic PSC-T cells. Finally, we use our PSC-T platform to discover novel insights into the contribution of T cell receptor specificity to T-lineage branching. An additional insight from this work is how sex-based differences in thymus regulation and T cell development arise, and the potential for PSC-T platforms to model sex-based differences in T cell development and function. Overall, these data represent a unique resource to investigate how human thymus niche biology guides T cell development, validate niche signaling insights via PSC-T technology development, and demonstrate a novel technology to study and perturb human immune system development.

Text

2024-12-10

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/89816

Biomedical Engineering

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/