IL-15-induced human DC efficiently prime melanoma-specific naive CD8+ T cells to differentiate into CTL.
Monocytes differentiate into dendritic cells (DC) in response to GM-CSF combined with other cytokines including IL-4 and IL-15. Here, we show that IL15-DC are efficient in priming naive CD8+ T cells to differentiate into melanoma antigen-specific cytotoxic T lymphocytes (CTL). While both melanoma peptide-pulsed IL15-DC and IL4-DC expand high-precursor frequency MART-1-specific CD8+ T cells after two stimulations in vitro, IL15-DC require much lower peptide concentration for priming. IL15-DC are more efficient in expanding gp100-specific CD8+ T cells and can expand CD8+ T cells specific for Tyrosinase and MAGE-3. CTL primed by IL15-DC are superior in their function as demonstrated by (i) higher IFN-gamma secretion, (ii) higher expression of Granzyme B and Perforin, and (iii) higher killing of allogeneic melanoma cell lines, most particularly the HLA-A*0201+ Sk-Mel-24 melanoma cells that are resistant to killing by CD8+ T cells primed with IL4-DC. Supernatants of the sonicated cells demonstrate unique expression of IL-1, IL-8 and IL-15. Therefore, membrane-bound IL-15 might contribute to enhanced priming by IL15-DC. Thus, IL-15 induces myeloid DC that are efficient in priming and maturation of melanoma antigen-specific CTL.
Dubsky
Peter
P
Baylor Institute for Immunology Research, Baylor NIAID Cooperative Center for Translational Research on Human Immunology and Biodefense, Dallas, TX 75204, USA.
Saito
Hiroaki
H
Leogier
Marylene
M
Dantin
Carole
C
Connolly
John E
JE
Banchereau
Jacques
J
Palucka
A Karolina
AK
D015703:Antigens, CD / Q000032:analysis / Q000378:metabolism; D000951:Antigens, Neoplasm / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D003601:Cytotoxicity Tests, Immunologic; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D053804:Granzymes / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D019409:Interleukin-15 / Q000378:metabolism / Q000494:pharmacology*; D015847:Interleukin-4 / Q000378:metabolism / Q000494:pharmacology; D016209:Interleukin-8 / Q000378:metabolism; D020014:K562 Cells; D017493:Leukocyte Common Antigens / Q000378:metabolism; D008070:Lipopolysaccharides / Q000494:pharmacology; D008214:Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D008545:Melanoma / Q000276:immunology*; D009000:Monocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014442:Monophenol Monooxygenase / Q000276:immunology; D009363:Neoplasm Proteins / Q000276:immunology; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D015703:Antigens, CD; D000951:Antigens, Neoplasm; C515370:CCR7 protein, human; D007375:Interleukin-1; D019409:Interleukin-15; D016209:Interleukin-8; D008070:Lipopolysaccharides; C072013:MAGEA3 protein, human; D009363:Neoplasm Proteins; D054400:Receptors, CCR7; D019707:Receptors, Chemokine; D015847:Interleukin-4; D007371:Interferon-gamma; D014442:Monophenol Monooxygenase; D017493:Leukocyte Common Antigens; D053804:Granzymes