DL4-μbeads induce T cell lineage differentiation from stem cells in a stromal cell-free system

Ashton C. Trotman-Grant, Mahmood Mohtashami, Joshua Sousa Casal, Elisa C. Martinez, Dylan Lee, Sintia Teichman, Patrick M. Brauer, Jianxun Han, Michele K. Anderson and Juan Carlos Zúñiga-Pflücker ()
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Ashton C. Trotman-Grant: University of Toronto
Mahmood Mohtashami: Sunnybrook Research Institute
Joshua Sousa Casal: University of Toronto
Elisa C. Martinez: Sunnybrook Research Institute
Dylan Lee: Sunnybrook Research Institute
Sintia Teichman: University of Toronto
Patrick M. Brauer: Sunnybrook Research Institute
Jianxun Han: Sunnybrook Research Institute
Michele K. Anderson: University of Toronto
Juan Carlos Zúñiga-Pflücker: University of Toronto

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: Abstract T cells are pivotal effectors of the immune system and can be harnessed as therapeutics for regenerative medicine and cancer immunotherapy. An unmet challenge in the field is the development of a clinically relevant system that is readily scalable to generate large numbers of T-lineage cells from hematopoietic stem/progenitor cells (HSPCs). Here, we report a stromal cell-free, microbead-based approach that supports the efficient in vitro development of both human progenitor T (proT) cells and T-lineage cells from CD34+cells sourced from cord blood, GCSF-mobilized peripheral blood, and pluripotent stem cells (PSCs). DL4-μbeads, along with lymphopoietic cytokines, induce an ordered sequence of differentiation from CD34+ cells to CD34+CD7+CD5+ proT cells to CD3+αβ T cells. Single-cell RNA sequencing of human PSC-derived proT cells reveals a transcriptional profile similar to the earliest thymocytes found in the embryonic and fetal thymus. Furthermore, the adoptive transfer of CD34+CD7+ proT cells into immunodeficient mice demonstrates efficient thymic engraftment and functional maturation of peripheral T cells. DL4-μbeads provide a simple and robust platform to both study human T cell development and facilitate the development of engineered T cell therapies from renewable sources.

Date: 2021
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DOI: 10.1038/s41467-021-25245-8

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