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Long-term in vivo provision of antigen-specific T cell immunity by programming hematopoietic stem cells

Yang, Lili and Baltimore, David (2005) Long-term in vivo provision of antigen-specific T cell immunity by programming hematopoietic stem cells. Proceedings of the National Academy of Sciences of the United States of America, 102 (12). pp. 4518-4523. ISSN 0027-8424. http://resolver.caltech.edu/CaltechAUTHORS:YANpnas05

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Abstract

A method to genetically program mouse hematopoietic stem cells to develop into functional CD8 or CD4 T cells of defined specificity in vivo is described. For this purpose, a bicistronic retroviral vector was engineered that efficiently delivers genes for both [alpha] and [beta] chains of T cell receptor (TCR) to hematopoietic stem cells. When modified cell populations were used to reconstruct the hematopoietic lineages of recipient mice, significant percentages of antigen-specific CD8 or CD4 T cells were observed. These cells expressed normal surface markers and responded to peptide antigen stimulation by proliferation and cytokine production. Moreover, they could mature into memory cells after peptide stimulation. Using TCRs specific for a model tumor antigen, we found that the recipient mice were able to partially resist a challenge with tumor cells carrying the antigen. By combining cells modified with CD8- and CD4-specific TCRs, and boosting with dendritic cells pulsed with cognate peptides, complete suppression of tumor could be achieved and even tumors that had become established would regress and be eliminated after dendritic cell/peptide immunization. This methodology of ‘‘instructive immunotherapy’’ could be developed for controlling the growth of human tumors and attacking established pathogens.


Item Type:Article
Additional Information:Contributed by David Baltimore, February 7, 2005. Freely available online through the PNAS open access option. We thank F. R. Carbone and W. R. Heath for the OT1 and OT2 TCR cDNAs; M. Bevan (University of Washington, Seattle) for the E.G7 tumor cell line; S. Kovats (City of Hope, Duarate, CA) for cell proliferation assays; E. Santiestevan for critical reading of the manuscript; and members of the D.B. laboratory for useful discussions. This work was supported by National Institute of Health Grant R01 GM39458.
Subject Keywords:HSC, hematopoietic stem cell; TCR, T cell receptor; BM, bone marrow; BMT, BM transfer; DC, dendritic cell; OVA, ovalbumin
Record Number:CaltechAUTHORS:YANpnas05
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:YANpnas05
Alternative URL:http://dx.doi.org/10.1073/pnas.0500600102
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:331
Collection:CaltechAUTHORS
Deposited By: Archive Administrator
Deposited On:02 Jun 2005
Last Modified:14 Nov 2014 19:18

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