IL-21 mediated Foxp3 suppression leads to enhanced generation of antigen-specific CD8+ cytotoxic T lymphocytes.

Publication Type:

Journal Article

Source:

Blood, Volume 111, Issue 1, p.229-35 (2008)

Keywords:

2008, Adoptive Transfer, Antigens, CD28, CD8-Positive T-Lymphocytes, Cell Division, Center-Authored Paper, Clinical Research Division, Cytokine Analysis Core Facility, Flow Cytometry Core Facility, Forkhead Transcription Factors, Humans, Immune Monitoring Core Facility, Immunologic Memory, Interleukin-2 Receptor alpha Subunit, Interleukins, Receptors, CCR7, Shared Resources, T-Lymphocytes, Cytotoxic, T-Lymphocytes, Regulatory

Abstract:

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 more than 150-fold decrease in Foxp3(+) cells to virtually undetectable levels and a more than 200-fold increase in antigen-specific cytotoxic T lymphocytes (CTLs). The extent of Foxp3 elimination and degree of expansion of antigen-specific CTLs shown in this study have not previously been achievable and are unique to IL-21. We demonstrate for the first time a possible mechanism for IL-21-mediated expansion of antigen-specific CTLs 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.