Limited T cell availability and proliferative exhaustion present major barriers to successful T cell-based immunotherapies and may potentially be overcome through the use of ''rejuvenated'' induced pluripotent stem cells derived from antigen-specific T cells (T-iPSCs). However, strict antigen specificity is essential for safe and efficient T cell immunotherapy. Here, we report that CD8ab T cells from human T-iPSCs lose their antigen specificity through additional rearrangement of the T cell receptor (TCR) a chain gene during the CD4/CD8 double positive stage of in vitro differentiation. CRISPR knockout of a recombinase gene in the T-iPSCs prevented this additional TCR rearrangement. Moreover, when CD8ab T cells were differentiated from monocyte-derived iPSCs that were transduced with an antigen-specific TCR, they showed monoclonal expression of the transduced TCR. TCR-stabilized, regenerated CD8ab T cells effectively inhibit tumor growth in xenograft cancer models. These approaches could contribute to safe and effective regenerative T cell immunotherapies.

Higher protein, particularly animal protein, was associated with lower risk of decline in higher-level functional capacity in older men. Animal protein intake may be a modifiable indicator for early detection and prevention of higher-level functional decline in elderly adults.

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