Purging Exhausted Virus-Specific CD8 T Cell Phenotypes by Somatic Cell Reprogramming.

TitlePurging Exhausted Virus-Specific CD8 T Cell Phenotypes by Somatic Cell Reprogramming.
Publication TypeJournal Article
Year of Publication2017
AuthorsChan J, Kim PY, Kranz E, Nagaoka Y, Lee YJ, Wen J, Elsaesser HJ, Qin M, Brooks DG, Ringpis G-E, S Y Chen I, Kamata M
JournalAIDS Res Hum Retroviruses
Volume33
IssueS1
PaginationS59-S69
Date Published2017 Nov
ISSN1931-8405
Abstract

Cytotoxic T cells are critical in controlling virus infections. However, continuous antigen stimulation and negative regulatory factors cause CD8 T cells to enter a dysfunctional state (T cell exhaustion), resulting in viral persistence. We hypothesized that the exhausted T cell state could be molecularly rejuvenated using a somatic cell reprogramming technology, which is technically able to convert any types of cells to induced pluripotent stem cells (iPSCs), to regenerate functional T cells capable of purging chronic infection. We generated a new mouse line (B6/129) in which every somatic cell contains four doxycycline-inducible reprogramming genes (Oct4, Klf4, Sox2, and c-Myc: OKSM), and infected them with lymphocytic choriomeningitis virus (LCMV) clone 13 to establish chronic infection. Exhausted LCMV-specific T cells isolated by flow sorting were successfully reprogrammed ex vivo into iPSCs in the presence of doxycycline. Upon injection into blastocysts and subsequent transfer into foster females, the reprogrammed cells differentiated into functional naive T cells that maintained their original antigen specificity. These results provide proof of concept that somatic cell reprogramming of exhausted T cells into iPSCs can erase imprints of their previous exhausted state and in turn regenerate functional virus-specific T cells.

DOI10.1089/aid.2017.0161
Alternate JournalAIDS Res. Hum. Retroviruses
PubMed ID29140111
PubMed Central IDPMC5684681
Grant ListP30 AI028697 / AI / NIAID NIH HHS / United States
R01 AI110200 / AI / NIAID NIH HHS / United States

Person Type: