Submitted May 9, 2007
Accepted September 10, 2007
IL-21 mediated FoxP3 suppression leads to enhanced generation of antigen-specific CD8+ CTL
Yongqing Li and Cassian Yee*
Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
Division of Oncology, Department of Medicine, University of Washington Medical Center, Seattle, WA, United States
* Corresponding author; email: cyee{at}fhcrc.org.
Efforts to reproducibly isolate tumor antigen-specific T cells from patients would be facilitated by removing immunoregulatory barriers. Using a human model for eliciting T cell responses to tumor-associated antigens, we develop a novel strategy that eliminates nearly all FoxP3-expressing cells through the combination of CD25 depletion and IL-21 treatment resulting in a > 150-fold decrease in FoxP3+ cells to virtually undetectable levels and a > 200 -fold increase in antigen-specific CTL. The extent of FoxP3 elimination and degree of expansion of antigen-specific CTL shown in this study have not previously been achievable and is unique to IL-21. We demonstrate for the first time a possible mechanism for IL-21-mediated expansion of antigen-specific CTL that involves suppression of FoxP3-expressing cells and reversal of inhibition to tumor-associated antigen-specific CTL generation in vitro. Taken together, the combination of CD25 depletion and IL-21 exposure, by releasing regulatory constraints, leads to markedly enhanced CTL induction and represents a robust strategy for the ex vivo generation of antigen specific T cells for adoptive cellular therapy.
