Biomedical subjects

Maria-Cristina Moldovan

Publications and source records attributed to Maria-Cristina Moldovan.

3 recordsLinked to original sources

PubMed2006

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.

Animals↗

PubMed2005

T cell synapse assembly: proteins, motors and the underlying cell biology.

A tantalizing feature of the 'immunological synapse' is the segregation of transmembrane proteins into activating clusters and their underlying signalosomes. The mechanisms by which transmembrane proteins are initially recruited to and then stably segregated at the synapse remains an outstanding question in the field; and one likely to reveal key modes of signaling regulation. Ongoing real-time imaging approaches and a refocusing of efforts upon understanding the basic cell biology of T cells have all contributed to a developing model of T cell behavior; elementary TCR-derived signaling quickly feeds back into the basic cellular programs controlling cell shape, adhesiveness, motility, as well as some poorly understood aspects of membrane fluidity and segregation. It is increasingly clear that the mechanisms for control at this level are shared between T cells and other cell types and may not be revealed in differential genomic screening. To this end, imaging-based genetic screens are now coming online to aid in identifying the ubiquitous proteins that function at polarized signaling surfaces.

Cell Communication↗

PubMed2002

CD4 dimers constitute the functional component required for T cell activation.

The CD4 molecule plays a key role in the development and activation of helper T cells. Dimerization and oligomerization is often a necessary step in the function of several cell surface receptors. Herein, we provide direct biochemical evidence confirming the presence of CD4 as dimers in transfected cells from hemopoetic and fibroblastic origin as well as in primary T cells. Such dimers are also observed with murine CD4 confirming selective pressure during evolution to maintain such a structure. Using a series of point mutations, we have precisely mapped the dimerization site at residues K318 and Q344 within the fourth extracellular domain of CD4. These residues are highly conserved and their mutation results in interference with dimer formation. More importantly, we demonstrate that dimer formation is essential for the coligand and coreceptor functions of CD4 in T cell activation. These data strongly suggest that CD4 dimerization is necessary for helper T cell function.

Amino Acid Sequence↗