T-Lymphocytes - Chronic Obstructive Pulmonary Disease - page 228

followed by the transport of the complex to the cytosol (160-162), proces-
sing in the proteasomes, transporting to the ER, and then loading onto
MHC Class I molecules and presenting to CD8 þ T-cells (162). A relatively
small proportion of the HSP-peptide complex internalized by the receptors
enters an acidic compartment and is loaded into the MHC Class II mole-
cules (64) leading to stimulation of CD4 þ T-cell (163). This will allow for
the simultaneous activation of CD4 þ and CD8 þ cells, an essential step in
CD8 þ activation, as we will see.
Heat shock proteins are released from cells undergoing lytic death, but
not from cells dying of apoptosis (157,64) and necrotic cell lysates and also
stressed cells have been reported to express cell surface HSP molecules
(64,157) that could activate DCs directly. The HSP appear to be a universal
mechanism for antigen capture and they permit a high-efficiency antigen
uptake through a receptor-mediated mechanism.
Another newly described form of cross-presentation of antigenic mate-
rial to the MHC Class I restricted pathway in DCs is by phagosomes
(164,165). This finding extends the competence of phagosomes previously
shown to be functional for the processing of MHC Class II complexes
(166). Phagosomes are formed after the phagocytosis of microbes, apoptotic
cells, and particulate matter by specialized cells: DCs, macrophages, and
neutrophils. It has been found that soon after their formation phagosomes
fuse with the endoplasmic reticulum (ER), site where MHC I molecules are
synthesized. The ER-phagosome fusion defines a compartment that brings
together all the MHC Class I processing and loading machinery, as well as
exogenous antigens in a single subcellular organelle (165). By doing so DCs
may focus all the cross-presentation machinery on the antigens relevant
for the initiation of most immune responses, that is those acquired by
phagocytosis.
Several important points arise from the mechanisms described. First,
exogenous antigens derived from infectious agents, dying cells, proteins
associated with inert particles (167,168), HSPs (84,169), and immune com-
plexes (170,171) acquired in the lung can be cross-presented to the DCs in
the draining lymph nodes and elicit a CD8 þ response. Second, a mechanism
exists to inform the DCs of two important events undergoing in the lung
parenchyma: (a) cell injury and necrosis, which information could be carried
by the HSPs; (b) apoptosis of parenchymal cells, which could be phagocy-
tosed by DC and equally cross-presented (164,165) inducing a CD8 þ
response.
Another important fact about cross-presentation, mentioned before, is
that the DC can present the same antigen through the MHC Class I path-
way to CD8 þ T-cells and through the MHC Class II pathway to the
CD4 þ T-cell (172,173). This is important because T-cell-dependent cyto-
toxic responses require the presentation of both Class II restricted and Class
I restricted pathways by the same DC (174). This has led to the idea that Th