Journal
EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 38, Issue 9, Pages 2557-2563Publisher
WILEY
DOI: 10.1002/eji.200737837
Keywords
Cbl; CD3; Lck; T cells; T-cell receptors
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Funding
- The National Programme for Research in Functional Genomics (FUGE)
- The Research Council of Norway
- The Norwegian Cancer Society
- Novo Nordic Foundation Committee
- European Union [037189]
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T cells with short interfering RNA-mediated Lck-knockdown (kd) display paradoxical hyper-responsiveness upon TCR ligation. We have previously reported a possible mechanism for T-cell activation in cells with low levels of Lck depending on Grb2-SOS1 recruitment to the zeta-chain of TCR/CD3 (Methi et al., Eur. J. Immunol. 2007, 37: 2539-2548). Here, we show that short interfering RNA-mediated targeting of Lck caused a dramatic reduction in c-Cbl phosphorylation and a general reduction in protein ubiquitination after TCR stimulation. Specifically, this resulted in reduced ubiquitination of the zeta-chain, yet internalization of TCR/CD3 appeared to be normal after receptor engagement. However, zeta-chain levels were elevated in Lck-kd cells, and confocal microscopy revealed reduced colocalization of CD3-containing vesicles with endosomal and lysosomal compartments. We hypothesize that prolonged stability of internalized T-cell receptor complex may result in extended signaling in T cells with low Lck levels.
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