Target Discovery and Validation Reviews and Protocols

Overview of Immune System 293
(unresponsiveness); downregulation of cell surface expression of TCR, BCR,
coreceptor molecules, or a combination; indifference; peripheral deletion; and
immunosuppression (31–33). Noteworthy is that the adaptive immune system
consists not only of immunostimulatory T-cells but also immunosuppressive
T-cells. So far, three subsets of immunosuppressive CD4+ T-cells have been
identified and the best-characterized population is defined by a constitutive
expression of interleukin (IL)-2 receptor α-chain. Although the majority of
these cells, known as regulatory T-cells (Treg cells) are generated in the thymus,
they may be generated in peripheral lymphoid organs under certain conditions
(Fig. 7). The physical interaction of activated Treg cells with CD4+ T-cells is
crucial in local and specific immunosuppression. However, the suppression can
be antigen nonspecific and independent of inhibitory cytokines such as IL 10
and TGFβ. Recent results indicated that depletion of Treg cells could lead to
autoimmunity in animal models. Additionally, dysfunction of these cells has
been linked to autoimmunity in humans (33).
In addition of playing a major role in the activation of T-cells, DCs also can
maintain both central and peripheral tolerance (34). Indeed, mature thymic DCs
are essential for the deletion of newly generated T-cells that have receptors
that recognize self-antigens with high affinity. By presenting tissue antigens to
naive T-cells in the absence of co-stimulatory signals, immature DCs induce
T-cell anergy/deletion or the development of inducible regulatory T-cells,
which produce IL-10 (Fig. 7). Interestingly, some studies indicated that peripheral
T-cell tolerance also could be maintained by receptor revision (35).
Consistent with the important role of GC in this process, information so far available
seems to indicate that TCR revision is restricted to CD4+ T-cell population.
In addition to central tolerance, potential autoreactive B-cells also are eliminated
in the periphery. However, if an autoreactive B-cell escapes clonal deletion or
receptor editing, or it is generated in the GC after somatic mutations, it should be
kept in check by the absence of the appropriate Th cell population, whose tolerance
is maintained at several levels (31).
5. Recognition of Self-Antigens Is Crucial for Both T- and B-Cell
Survival: How Strong Can the Interaction Be?
Recent studies indicated that naive peripheral T-cells bearing TCRs that fail to
interact with MHC molecules plus self-peptides have a shortened life-span and do
not undergo homeostatic proliferation to maintain the proper balance of lymphoid
cell populations (36,37). To survive, peripheral naive T-cells require the recognition
of self-peptide/MHC complexes. TCRs transduce survival signals upon binding
to self-MHC molecules. These results underlie the important roles played
by the selecting self-peptides. Notably, this self-recognition constitutes a permanent
danger because under certain conditions (e.g., peptide concentration or