IL-21 influences the frequency, phenotype, and affinity of the antigen-specific CD8 T cell response.
IL-21, a newly described cytokine belonging to the IL-2 gamma-chain receptor cytokine family (that includes IL-2, IL-7, and IL-15), has been described as an important regulator of the cellular immune response. In this study, the role of IL-21 in the generation of a human Ag-specific CD8+ T cell response is characterized by tracking a rare, but measurable population of self-Ag-specific T cells in vitro. Autologous dendritic cells pulsed with the melanoma antigen recognized T cells 1 self-peptide were used to stimulate CD8+ T cells from HLA-A2+ healthy donors and melanoma patients. We demonstrate that exposure to IL-21 increased the total number of MART-1-specific CD8+ T cells that could be elicited by >20-fold and, at the clonal level, enriched for a population of high-affinity CD8+ T cells with a peptide dose requirement more than 1 log(10)-fold less than their untreated counterparts. Phenotypic analysis of T cells from IL-21-treated cultures revealed a unique population of CD45RO+ CD28(high) CD8+ T cells, a phenotype that was stable for at least 4 wk after IL-21 exposure. These CD28(high) CD8+ T cells produced IL-2 upon Ag stimulation and represent potential helper-independent CTLs. Our studies demonstrate a significant role for IL-21 in the primary Ag-specific human CTL response and support the use of IL-21 in the ex vivo generation of potent Ag-specific CTLs for adoptive therapy or as an adjuvant cytokine during in vivo immunization against tumor Ags.
Li
Yongqing
Y
Program in Immunology, Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
Bleakley
Marie
M
Yee
Cassian
C
D000276:Adjuvants, Immunologic / Q000502:physiology*; D018106:CD28 Antigens / Q000096:biosynthesis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002448:Cell Adhesion / Q000276:immunology; D002460:Cell Line; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002999:Clone Cells; D003601:Cytotoxicity Tests, Immunologic / Q000379:methods; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D006801:Humans; D016130:Immunophenotyping / Q000379:methods; D007378:Interleukins / Q000502:physiology*; D017493:Leukocyte Common Antigens / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D018655:Lymphocyte Count; D008545:Melanoma / Q000276:immunology / Q000473:pathology; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D000098546:Interleukin-21
D000276:Adjuvants, Immunologic; C515370:CCR7 protein, human; D018106:CD28 Antigens; D018984:Epitopes, T-Lymphocyte; D007378:Interleukins; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D017493:Leukocyte Common Antigens; D000098546:Interleukin-21