Biomedical Engineering Reference
In-Depth Information
memory. The mechanisms that account for these divergent responses remain
uncertain, but are probably mostly related to the amount of signal T-cells
received by interacting with DCs (205). These responses are determined
by: (a) the concentration of peptide-MHC complexes, which determines
the rate of TCR triggering (206); (b) the concentration of costimulatory
molecules, which determines the extent of signal amplification (207); and
(c) the duration of the interaction between T-cells and DCs, which deter-
mines for how long the signal is accumulated (205).
Hierarchical thresholds of stimulation have been defined for cell
proliferation, differentiation, and death (208-210). These thresholds depend
on the density of antigen-presenting DCs in the local lymphoid tissue, which
determines the frequency and duration of T-cell stimulation and hence the
signal strength and the T-cell fate. If a DC presents low levels of antigen,
expresses low levels of costimulatory molecules, does not produce cytokines,
and consequently can deliver only a low level of stimulation, the T-cell
would be eliminated by apoptosis (205). In contrast, when peripheral tissues
are inflamed, the large numbers of DCs recruited are activated, mature and
migrate to the lymph nodes. There they could present high levels of antigen
and costimulatory molecules and produce IL-12, so providing optimal
conditions for strong and sustained T-cell stimulation.
However, because the DC-T-cell interactions are stochastic, it is
conceivable that not all T-cells receive the same level of stimulation, even
in the same proliferating clone (205). The T-cells that have received high sig-
nal strength acquire tissue-homing capacity can enter inflamed tissues, and
exert effector function (211) for extended periods of time (212), either
because they are long lived or are continuously replaced, but they do not
seem to divide in situ. At low signal strength, na
¨
ve T-cells proliferate, but
do not acquire effector function and retain lymph node homing capacity
or become regulatory CD4
þ
CD25
þ
suppressor cells (213).
It can be seen that the highly variable stimulatory conditions found in
lymphoid organs and the stochastic nature of DC-T-cell interactions would
lead to the generation of many T-cell fates. Clearly the balance of these
resulting T-cell populations will determine the fitness and overall number
of cells homing to the inflamed tissue, their survival and ultimately, their
ability to clear a pathogen (205), or in our case produce lung damage
(Fig. 8).
Another emerging topic in peripheral tolerance is the role of CD4
þ
CD25
þ
suppressor cells. These cells seem to be generated when T-cells
are partially activated by encounter with antigen by the DCs, in the absence
of or insufficient costimulatory signals or contact with DC, not ''fully
loaded'' with antigens (see above). These lymphocytes have been considered
anergic, however, it is becoming increasingly clear that they are likely to
have a regulatory function. These are cells that protect against pathological
or clinical undesirable inflammatory immune responses, having the ability to
