26 research outputs found
Force Generation upon T Cell Receptor Engagement
T cells are major players of adaptive immune response in mammals. Recognition of
an antigenic peptide in association with the major histocompatibility complex at
the surface of an antigen presenting cell (APC) is a specific and sensitive
process whose mechanism is not fully understood. The potential contribution of
mechanical forces in the T cell activation process is increasingly debated,
although these forces are scarcely defined and hold only limited experimental
evidence. In this work, we have implemented a biomembrane force probe (BFP)
setup and a model APC to explore the nature and the characteristics of the
mechanical forces potentially generated upon engagement of the T cell receptor
(TCR) and/or lymphocyte function-associated antigen-1 (LFA-1). We show that upon
contact with a model APC coated with antibodies towards TCR-CD3, after a short
latency, the T cell developed a timed sequence of pushing and pulling forces
against its target. These processes were defined by their initial constant
growth velocity and loading rate (force increase per unit of time). LFA-1
engagement together with TCR-CD3 reduced the growing speed during the pushing
phase without triggering the same mechanical behavior when engaged alone.
Intracellular Ca2+ concentration
([Ca2+]i) was monitored simultaneously
to verify the cell commitment in the activation process.
[Ca2+]i increased a few tens of seconds
after the beginning of the pushing phase although no strong correlation appeared
between the two events. The pushing phase was driven by actin polymerization.
Tuning the BFP mechanical properties, we could show that the loading rate during
the pulling phase increased with the target stiffness. This indicated that a
mechanosensing mechanism is implemented in the early steps of the activation
process. We provide here the first quantified description of force generation
sequence upon local bidimensional engagement of TCR-CD3 and discuss its
potential role in a T cell mechanically-regulated activation process
Deciphering the pathway from the TCR to NF-kappaB.
A major regulator of lymphocyte survival and activation is the transcription factor nuclear factor-kappaB (NF-kappaB). Controlled activation of NF-kappaB is essential for the immune and inflammatory response as well as for cell proliferation and protection against apoptosis. The NEMO/IkappaB kinase (IKK) complex is the central integrator of most stimuli leading to NF-kappaB activation, but a detailed knowledge of the upstream events is available only for a limited number of stimuli. In particular, although most players have probably been identified, relatively little is known about the detailed molecular mechanisms involved in the cascade leading to NF-kappaB activation following engagement of the T-cell receptor by a foreign antigen. In this review, we discuss recent insights into this specific signal transduction cascade, and the way it is controlled both spatially and temporally