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

Abstract

Adoptive 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.

Multicolor Staining of Globin Subtypes Reveals Impaired Globin Switching During Erythropoiesis in Human Pluripotent Stem Cells

“…To differentiate hES/hiPSCs into hematopoietic cells, we used our previously established protocol [21][22][23]. After pretreating mouse mesenchymal feeder C3H10T1/2 cells with mitomycin C, small clumps (approximately 100 cells) of hES/iPSCs (suspended in phosphate-buffered saline [PBS] containing 0.25% trypsin, 1 mM CaCl 2 , and 20% knockout serum replacement) were transferred onto the C3H10T1/2 cells (8.0 3 10 5 cells per a 100-mm dish) and cultured in differentiation medium supplemented with 20 ng/ml vascular endothelial growth factor for 14 days (day 214 to day 0).…”

“…We have developed a coculture system with which human ESCs or iPSCs can be differentiated into multipotent hematopoietic progenitors capable of yielding megakaryocytes, erythroblasts, or lymphocytes [21][22][23]27]. Using this culture system, we first sought to generate erythroblasts from the H1 and KhES-3 hESC lines using the protocol diagrammed in Figure 1A and from human CB-CD34 + cells using the protocol diagrammed in Figure 1B.…”

Functional Attributes of Responding T Cells in HCV Infection: The Recent Advances in Engineering Functional Antiviral T Cells

“…T cells. There was also evidence that such ''rejuvenated'' cells possessed antigen-specific killing activity and exhibited TCR gene rearrangement patterns identical to those of the original T cell clone from the patient (Nishimura et al 2013). Furthermore, they showed that re-differentiation of these cells produced CD8…”

“…Similar to ESCs, iPSCs have the capacity for self-renewal and could potentially derive unlimited induction of antigen-specific juvenile T cells. Two stem cell groups have explored this novel approach to reprogram an exhausted immune system as treatment of cancer and chronic infection (Nishimura et al 2013;Vizcardo et al 2013). Both groups successfully established protocols to reprogram human antigen-specific CD8 ?…”

Novel TPO receptor agonist TA-316 contributes to platelet biogenesis from human iPS cells

“…5 In that context, we established an in vitro iPS-Sac culture system for differentiation into megakaryocytes (MKs, platelet precursors), 5,6 which also yields T lymphocytes. 7 Unfortunately, the efficiency of the MK production is extremely low. 5 We therefore established self-renewing immortalized MK progenitor cell lines (imMKCLs) from hiPSCs as a starting material of platelet supply, because they exhibit a capacity for the long-term expansion of MKs that produce a substantial yield of platelets.…”