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Generation of rejuvenated antigen-specific T cells by reprogramming to pluripotency and redifferentiation

Cell Stem Cell 12 2013, 114-126, doi:
Nishimura T, Kaneko S, Kawana-Tachikawa A, Tajima Y, Goto H, Zhu D, Nakayama-Hosoya K, Iriguchi S, Uemura Y, Shimizu T, Takayama N, Yamada D, Nishimura K, Ohtaka M, Watanabe N, Takahashi S, Iwamoto A, Koseki H, Nakanishi M, Eto K, Nakauchi H.
Division of Stem Cell Therapy, Center for Stem Cell Biology and Regenerative Medicine, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.

The human immune system is composed of multiple types of immune cells. Cytotoxic T cells are the front-line warriors combating pathogens and diseases. T-cell immune response is initiated most efficiently when naïve CD8+ cytotoxic T cells are activated by their cognate antigens. In chronically ill patients, because of repeated stimulation by pathogenic antigens, T cells fall into a state known as "cellular senescence" or "exhaustion," a type of aged state. Such replicative senescence is also a major issue for adoptive cell therapy using ex vivo-expanded antigen-specific cytotoxic T cells.

In the current study, Professor Hiromitsu Nakauchi and his research group at the Institute of Medical Science, the University of Tokyo demonstrated the rejuvenation of exhausted T cells by passing through induced pluripotent stem (iPS) cell intermediate. The researchers prepared T cells from HIV-infected patients and reprogrammed them into iPS cells (T-iPSCs). Furthermore, they showed that redifferentiation of these cells produced mature CD8+ T cells that recognize their original cognate antigen and exhibit long telomeres, the features of rejuvenation. This is significant because exhaustion of T cells limits cell expansion and efficiency of therapeutic use.

The system established here provides "rejuvenated and regenerated" antigen-specific T cells by taking advantage of reprogramming technology. These findings suggest that manipulating T cells using iPSC techniques could be useful for future development of more effective immune therapies.