IL-21 mediated Foxp3 suppression leads to enhanced generation of antigen-specific CD8+ cytotoxic T lymphocytes.
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.
Li
Yongqing
Y
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Yee
Cassian
C
D019264:Adoptive Transfer; D018106:CD28 Antigens / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D002455:Cell Division / Q000276:immunology; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007156:Immunologic Memory; D066298:In Vitro Techniques; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D007378:Interleukins / Q000276:immunology / Q000378:metabolism*; D054400:Receptors, CCR7 / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000378:metabolism; D000098546:Interleukin-21
C515370:CCR7 protein, human; D018106:CD28 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; D007378:Interleukins; D054400:Receptors, CCR7; D000098546:Interleukin-21