Triggering of T cell activation via CD4 dimers.
The onset of activation in Th cells is triggered by localized co-engagement of TCRs and the coreceptor CD4. A CD4 crystal suggested that CD4 may form dimers in some circumstances. In this study, we use live-cell fluorescence resonance energy transfer imaging to demonstrate that CD4 dimers are present at a basal level on the cell surface and accumulate at the synapse. Mechanistically, we reveal two conditions under which dimers are highly relevant. First, CD4 dimers are more proficient in mediating prolonged cell contacts with APCs in the presence or absence of Ag. This is consistent with a model whereby the dimer functions to increase T-APC avidity. Second, we show that dimer mutations result in an increased level of an inactive lckTyr(505) bound to the CD4 molecule relative to dimer-competent CD4. We also find a consistent defect in signaling onset in these cells. This supports a role for CD4 dimerization in maintaining active signaling machinery. We suggest that modulation of the dimer/monomer ratio may permit tuning of activation thresholds during initial engagement.
Moldovan
Maria-Cristina
MC
Department of Microbiology and Immunology, McGill University, Montréal, Canada.
Sabbagh
Laurent
L
Breton
Gaëlle
G
Sékaly
Rafick-Pierre
RP
Krummel
Matthew F
MF
D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D019281:Dimerization; D031541:Fluorescence Resonance Energy Transfer; D008213:Lymphocyte Activation / Q000276:immunology*; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D011485:Protein Binding; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*
D015704:CD4 Antigens; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D002118:Calcium