Generation of Rejuvenated Antigen-Specific T Cells by Reprogramming to Pluripotency and Redifferentiation

SummaryAdoptive immunotherapy with functional T cells is potentially an effective therapeutic strategy for combating many types of cancer and viral infection. However, exhaustion of antigen-specific T cells represents a major challenge to this type of approach. In an effort to overcome this problem, we reprogrammed clonally expanded antigen-specific CD8+ T cells from an HIV-1-infected patient to pluripotency. The T cell-derived induced pluripotent stem cells were then redifferentiated into CD8+ T cells that had a high proliferative capacity and elongated telomeres. These “rejuvenated” cells possessed antigen-specific killing activity and exhibited T cell receptor gene-rearrangement patterns identical to those of the original T cell clone from the patient. We also found that this method can be effective for generating specific T cells for other pathology-associated antigens. Thus, this type of approach may have broad applications in the field of adoptive immunotherapy.

Graphical AbstractFigure optionsDownload high-quality image (328 K)Download as PowerPoint slideHighlights
► Reprogramming of antigen-specific T cells to generate iPSCs (T-iPSCs)
► Redifferentiation of CD8+ T cells, with original antigen specificity, from T-iPSCs
► Newly differentiated T cells show high proliferation and elongated telomeres
► T cell antigen-specific cytotoxicity is maintained