TCR down-regulation boosts T-cell-mediated cytotoxicity and protection against poxvirus infections
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TCR down-regulation boosts T-cell-mediated cytotoxicity and protection against poxvirus infections. / Hansen, Ann Kathrine; Regner, Matthias; Bonefeld, Charlotte Menne; Boding, Lasse; Kongsbak-Wismann, Martin; Ødum, Niels; Müllbacher, Arno; Geisler, Carsten; von Essen, Marina Rode.
In: European Journal of Immunology, Vol. 41, No. 7, 2011, p. 1948-1957.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - TCR down-regulation boosts T-cell-mediated cytotoxicity and protection against poxvirus infections
AU - Hansen, Ann Kathrine
AU - Regner, Matthias
AU - Bonefeld, Charlotte Menne
AU - Boding, Lasse
AU - Kongsbak-Wismann, Martin
AU - Ødum, Niels
AU - Müllbacher, Arno
AU - Geisler, Carsten
AU - von Essen, Marina Rode
N1 - Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
PY - 2011
Y1 - 2011
N2 - Cytotoxic T (Tc) cells play a key role in the defense against virus infections. Tc cells recognize infected cells via the T-cell receptor (TCR) and subsequently kill the target cells by one or more cytotoxic mechanisms. Induction of the cytotoxic mechanisms is finely tuned by the activation signals from the TCR. To determine whether TCR down-regulation affects the cytotoxicity of Tc cells, we studied TCR down-regulation-deficient CD3¿LLAA mice. We found that Tc cells from CD3¿LLAA mice have reduced cytotoxicity due to a specific deficiency in exocytosis of lytic granules. To determine whether this defect was reflected in an increased susceptibility to virus infections, we studied the course of ectromelia virus (ECTV) infection. We found that the susceptibility to ECTV infection was significantly increased in CD3¿LLAA mice with a mortality rate almost as high as in granzyme B knock-out mice. Finally, we found that TCR signaling in CD3¿LLAA Tc cells caused highly increased tyrosine phosphorylation and activation of the c-Cbl ubiquitin ligase, and that the impaired exocytosis of lytic granules could be rescued by the knockdown of c-Cbl. Thus, our work demonstrates that TCR down-regulation critically increases Tc cell cytotoxicity and protection against poxvirus infection.
AB - Cytotoxic T (Tc) cells play a key role in the defense against virus infections. Tc cells recognize infected cells via the T-cell receptor (TCR) and subsequently kill the target cells by one or more cytotoxic mechanisms. Induction of the cytotoxic mechanisms is finely tuned by the activation signals from the TCR. To determine whether TCR down-regulation affects the cytotoxicity of Tc cells, we studied TCR down-regulation-deficient CD3¿LLAA mice. We found that Tc cells from CD3¿LLAA mice have reduced cytotoxicity due to a specific deficiency in exocytosis of lytic granules. To determine whether this defect was reflected in an increased susceptibility to virus infections, we studied the course of ectromelia virus (ECTV) infection. We found that the susceptibility to ECTV infection was significantly increased in CD3¿LLAA mice with a mortality rate almost as high as in granzyme B knock-out mice. Finally, we found that TCR signaling in CD3¿LLAA Tc cells caused highly increased tyrosine phosphorylation and activation of the c-Cbl ubiquitin ligase, and that the impaired exocytosis of lytic granules could be rescued by the knockdown of c-Cbl. Thus, our work demonstrates that TCR down-regulation critically increases Tc cell cytotoxicity and protection against poxvirus infection.
U2 - 10.1002/eji.201141413
DO - 10.1002/eji.201141413
M3 - Journal article
C2 - 21590764
VL - 41
SP - 1948
EP - 1957
JO - European Journal of Immunology
JF - European Journal of Immunology
SN - 0014-2980
IS - 7
ER -
ID: 33732643