Human γδ thymocytes are functionally immature and differentiate into cytotoxic type 1 effector T cells upon IL-2/IL-15 signaling.
Cytotoxicity and IFN-γ production by human γδ T cells underlie their potent antitumor functions. However, it remains unclear where and how human γδ T cells acquire these key effector properties. Given the recent disclosure of a major contribution of the thymus to murine γδ T cell functional differentiation, in this study we have analyzed a series of human pediatric thymuses. We found that ex vivo-isolated γδ thymocytes produced negligible IFN-γ and lacked cytolytic activity against leukemia cells. However, these properties were selectively acquired upon stimulation with IL-2 or IL-15, but not IL-4 or IL-7. Unexpectedly, TCR activation was dispensable for these stages of functional differentiation. The effects of IL-2/IL-15 depended on MAPK/ERK signaling and induced de novo expression of the transcription factors T-bet and eomesodermin, as well as the cytolytic enzyme perforin, required for the cytotoxic type 1 program. These findings have implications for the manipulation of γδ T cells in cancer immunotherapy.
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, 1649-028 Lisbon, Portugal.
Julie C
JC
Ribot
Sérgio T
ST
Ribeiro
Daniel V
DV
Correia
Ana E
AE
Sousa
Bruno
B
Silva-Santos
D002454:Cell Differentiation / Q000502:physiology*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007167:Immunotherapy; D007223:Infant; D007231:Infant, Newborn; D019409:Interleukin-15 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D007376:Interleukin-2 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D008297:Male; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000628:therapy; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D000098815:T-bet Transcription Factor
C491198:Eomes protein, mouse; C569274:IL15 protein, human; C508594:IL2 protein, human; D019409:Interleukin-15; D007376:Interleukin-2; D016692:Receptors, Antigen, T-Cell, gamma-delta; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor