Triggering of T cell activation via CD4 dimers

The Journal of Immunology : Official Journal of the American Association of Immunologists
Maria-Cristina MoldovanMatthew F Krummel

Abstract

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.

References

May 1, 1989·Proceedings of the National Academy of Sciences of the United States of America·J M RojoC A Janeway
Mar 1, 1987·Proceedings of the National Academy of Sciences of the United States of America·O LeoJ A Bluestone
Apr 1, 1984·The Journal of Experimental Medicine·J L GreensteinS J Burakoff
Jul 3, 1995·Proceedings of the National Academy of Sciences of the United States of America·T SakihamaE L Reinherz
Sep 15, 1993·Proceedings of the National Academy of Sciences of the United States of America·W S PearD Baltimore
Jun 1, 1993·International Immunology·S Weber, K Karjalainen
May 1, 1996·The Journal of Experimental Medicine·D A VignaliJ L Strominger
Apr 1, 1996·The Journal of Experimental Medicine·K VidalP M Allen
Apr 1, 1996·The Journal of Experimental Medicine·S ValituttiA Lanzavecchia
Jul 16, 1996·Biochemical and Biophysical Research Communications·T SatohZ Huang
Jan 5, 1999·The Journal of Experimental Medicine·T ProftJ D Fraser
Aug 24, 1999·European Journal of Immunology·G W LynchA L Cunningham
Aug 30, 2000·Proceedings of the National Academy of Sciences of the United States of America·C WülfingM M Davis
Dec 7, 2000·The Journal of Biological Chemistry·Y XiongE Reinherz
Jun 5, 2001·Nature Reviews. Molecular Cell Biology·J Lippincott-SchwartzA Kenworthy
Jun 14, 2001·Methods : a Companion to Methods in Enzymology·A K Kenworthy
Nov 8, 2001·The Journal of Immunology : Official Journal of the American Association of Immunologists·M M MorganJ K Burkhardt
Feb 6, 2002·Nature Immunology·Amy D HoldorfAndrey S Shaw
Jun 22, 2002·The Journal of Immunology : Official Journal of the American Association of Immunologists·David SanchoFrancisco Sánchez-Madrid
Oct 25, 2002·Nature·Darrell J IrvineMark M Davis
Nov 22, 2002·The Journal of Immunology : Official Journal of the American Association of Immunologists·Maria-Cristina MoldovanRafick-Pierre Sékaly
Feb 6, 2004·Immunology Letters·Paola PizzoAntonella Viola

❮ Previous
Next ❯

Citations

Nov 27, 2008·Molecular Imaging and Biology : MIB : the Official Publication of the Academy of Molecular Imaging·Feng ZhangCheng He
Aug 22, 2018·Scientific Reports·Victoria JunghansPeter Jönsson
Jul 2, 2009·Expert Opinion on Therapeutic Patents·Alexander M Abdelnoor
May 23, 2012·The Journal of Immunology : Official Journal of the American Association of Immunologists·Michal Jaron-MendelsonAngel Porgador
Sep 16, 2008·European Journal of Immunology·Andrej ManteiAlexander Scheffold
Nov 13, 2020·Frontiers in Cell and Developmental Biology·Alexander M MørchMichael L Dustin

❮ Previous
Next ❯

Related Concepts

Related Feeds

Calcium & Bioenergetics

Bioenergetic processes, including cellular respiration and photosynthesis, concern the transformation of energy by cells. Here is the latest research on the role of calcium in bioenergetics.

Brain developing: Influences & Outcomes

This feed focuses on influences that affect the developing brain including genetics, fetal development, prenatal care, and gene-environment interactions. Here is the latest research in this field.