Cancer Immune Therapy Edited by G. Stuhler and P. Walden ...

Box 10.1 Thymic selection of Tcells and the
generation of tolerance to self. The immune system
has evolved to ignore self antigens to prevent
the onset of autoimmune disease through the
generation of tolerance. (A) Negative selection of
Tcells with TCRs that recognize self antigens eradicates
Tcells with autoimmune capability. Naive
Tcells express TCRs which can recognize peptides
in the context of MHC molecules presented
by thymic DCs [91, 92]. Any Tcell with a TCR that
binds to an MHC molecule expressing an epitope
derived from a self antigen in the thymus is induced
to die by apoptosis. Thus, tolerance to self
peptides is established by negative selection of
autoreactive Tcells in the thymus (central tolerance).
Other less well-defined mechanisms may
10.2 Evolutionary Tuning
also exist to establish tolerance to self antigens in
the peripheral circulation, possibly by a population
of DCs which continually display self antigens
to Tcells in the lymph nodes in a tolerogenic
rather activating environment [6, 61]. (B) Any
other Tcells are not negatively selected in the thymus,
either because they recognize self antigens
that do not have access to the thymus, or that are
not expressed until after generation of the Tcell
repertoire in the thymus, or because they have
TCR which recognize non-self epitopes. Alternatively,
they have a TCR that binds only weakly to a
self peptide displayed in the thymus, allowing the
Tcell to escape thymic selection. Those Tcells
that do not recognize any self antigens pass to
the periphery to seek non-self antigens.
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