Identification of an indispensable role for tyrosine kinase 2 in CTL-mediated tumor surveillance.
We showed previously that Tyk2(-/-) natural killer cells lack the ability to lyse leukemic cells. As a consequence, the animals are leukemia prone. Here, we show that the impaired tumor surveillance extends to T cells. Challenging Tyk2(-/-) mice with EL4 thymoma significantly decreased disease latency. The crucial role of Tyk2 for CTL function was further characterized using the ovalbumin-expressing EG7 cells. Tyk2(-/-) OT-1 mice developed EG7-induced tumors significantly faster compared with wild-type (wt) controls. In vivo assays confirmed the defect in CD8(+) cytotoxicity on Tyk2 deficiency and clearly linked it to type I IFN signaling. An impaired CTL activity was only observed in IFNAR1(-/-) animals but not on IFNgamma or IL12p35 deficiency. Accordingly, EG7-induced tumors grew faster in IFNAR1(-/-) and Tyk2(-/-) but not in IFNgamma(-/-) or IL12p35(-/-) mice. Adoptive transfer experiments defined a key role of Tyk2 in CTL-mediated tumor surveillance. In contrast to wt OT-1 cells, Tyk2(-/-) OT-1 T cells were incapable of controlling EG7-induced tumor growth.
Simma
Olivia
O
Institute of Pharmacology, Medical University of Vienna, Waehringerstrasse 13A, Vienna, Austria.
Zebedin
Eva
E
Neugebauer
Nina
N
Schellack
Carola
C
Pilz
Andreas
A
Chang-Rodriguez
Souyet
S
Lingnau
Karen
K
Weisz
Eva
E
Putz
Eva Maria
EM
Pickl
Winfried F
WF
Felzmann
Thomas
T
Müller
Mathias
M
Decker
Thomas
T
Sexl
Veronika
V
Stoiber
Dagmar
D
D000818:Animals; D045744:Cell Line, Tumor; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005260:Female; D007157:Immunologic Surveillance; D007370:Interferon Type I / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D018664:Interleukin-12 / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000201:enzymology* / Q000276:immunology*; D053634:TYK2 Kinase / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D013945:Thymoma / Q000201:enzymology / Q000276:immunology*; D013953:Thymus Neoplasms / Q000201:enzymology / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; C508032:Ifnar1 protein, mouse; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta; D018664:Interleukin-12; D007371:Interferon-gamma; D053634:TYK2 Kinase; C499356:Tyk2 protein, mouse