T-Lymphocytes - Chronic Obstructive Pulmonary Disease - page 227

The CD8 þ CTLs recognize their target antigen as peptide fragments
derived inside the cell and presented by the MHC Class I loci. Consequently,
the MHC Class I-restricted presentation pathway is recognized as the
''endogenous'' pathway and this term distinguishes Class I presentation
from the largely extracellular or ''exogenous'' MHC Class II-restricted pre-
sentation required for CD4 þ T-helper (Th) cell recognition (10). Problems
arise if the classical paradigm of ''endogenous-only'' Class I presentation
is used to describe a CTL response to a virus, or other cell-derived antigen ori-
ginating within a peripheral tissue like the lung. Na¨ve T-cells are not expected
to enter nonlymphoid areas of the body, but rather recirculate between the
secondary lymphoid organs (see above). To penetrate the lung harboring
antigen-producing cells (like injured or virus-infected cells), CD8 þ CTLs
must be first primed in draining lymph nodes (CD8 þ cannot be primed in
the lung) and for this priming to take place antigen must make its way into
draining lymph nodes (150). It is now evident that ''exogenous'' antigens
can also access the MHC Class I processing pathway, and present antigens
to the CD8 þ T-cell, a phenomenon recognized as ''cross-presentation'' or
''cross-priming'' (151,152). By examining T-cell responses to antigens
expressed exclusively in nonlymphoid compartments, in specially designed
transgenic animals, it has been clearly shown that CD8 þ T-cell activation
occurs exclusively within the lymph nodes that drained the site of active
antigen synthesis (150).
Cell-associated proteins (153,154) and particulate antigens (155,156)
are much more effective at Class I-restricted CD8 þ T-cells priming that
are simple soluble molecules and it can be speculated that these antigenic
forms mimic the tissue debris associated with viral infections. Cross-
presentation might have been a mechanism primarily designed for periph-
eral viral infections to prime CTL responses in a central lymphoid compart-
ment and for particulate antigens, in the form of damaged cells, to gain
access to DCs (157).
There are a number of mechanisms that provide exogenous antigen
access to the MHC Class I presentation pathway, the HSP pathways being
the best described. Heat shock proteins (discussed above) are abundant
soluble intracellular proteins that bind peptides including antigenic peptides
generated within cells, and it has been conclusively shown (157) that
HSP-peptide complexes elicit CD8 þ T-cell responses in spite of exogenous
administration, a route that typically would elicit CD4 þ T-cell responses as
they are normally presented through the ''exogenous'' MHC Class II
pathway.
The ability of the HSP chaperoned peptides to cross-prime CD8 þ
T-cell responses is based on the ability of HSPs (gp96, HSP90, HSP70,
and calreticulin) to interact with macrophages and DCs through common
receptors, CD91 (158,159) and also TL-4 (159). This interaction leads to
internalization of the complexes into a nonacidic endosomal compartment