Conversion of p56(lck) to p60(lck) in human peripheral blood T lymphocytes is dependent on co- stimulation through accessory receptors: involvement of phospholipase C, protein kinase C and MAP-kinases in vivo.
Activation of T cells requires co-stimulation of the TCR and accessory receptors like CD2, CD4, CD8, CD11a or CD28. Engagement of the TCR without co-stimulation results in anergy / apoptosis. Here we show that induction of the shift of the tyrosine kinase p56lck from 56 kDa to apparent 60 kDa in resting human peripheral blood T cells (PBT) is strictly dependent on co-stimulation through both TCR and accessory receptors. In contrast, triggering of the TCR alone is only sufficient to induce the lck shift in preactivated cells like T cell clones or the T lymphoma line Jurkat. Our studies predict an involvement of a phospholipase C isoform which surprisingly acts downstream of a phorbolester-sensitive, H7-insensitive protein kinase C. Inhibition of the lck shift in vivo by U73122, a specific inhibitor of phospholipase C, correlates with reduced activation of the MAP-kinases ERK1 / 2. Moreover, the MEK1-specific inhibitor PD98059 blocks the lck shift in vivo. These findings demonstrate that activation of the MEK1-ERK1 / 2 pathway is required for lck conversion in vivo. The lck shift is not inducible by co-stimulation through acidic sphingomyelinase or ceramides which even prevent ERK2 activation in PBT. Moreover, it is resistant to treatment with W7, KN62 and cyclosporin A.
Schröder
A J
AJ
Institute for Immunology, University of Heidelberg, Germany.
Quehl
P
P
Müller
J
J
Samstag
Y
Y
D006801:Humans; D008213:Lymphocyte Activation; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000276:immunology*; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000276:immunology; D011493:Protein Kinase C / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D010738:Type C Phospholipases / Q000276:immunology*
D011948:Receptors, Antigen, T-Cell; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D010738:Type C Phospholipases