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V. Barnaba - Innovative strategies eliciting CD8 T cell responses by exploiting proteomic analysis and improving cross-presentation
In this project, we have examined the proteomic profile
of apoptotic T cells by the combination of twodimensional
electrophoresis (2DE) and matrix assisted
laser desorption ionization-time of flight-mass
spectrometry (MALDI-TOF-MS) analyses, and
found that the apoptotic T cell proteome is represented
by several fragments of cytoskeleton-associated
proteins, which showed antigenic properties
with respect to human CD8+ T cells in vivo. In addition,
we have defined a new role of caspases by which
they facilitate cross-presentation of apoptotic cellassociated
antigens. Our data suggest that caspase
cleavage allows the release of cell-associated antigens
(possibly long-lived) from the cellular matrix
and their subsequent delivery to the cross-presentation
pathway. The unveiling of a new antigenic
repertoire in apoptotic cells caused by caspasedependent
cleavage may have a major role in inducing
either cross-tolerance (in the steady state) or
cross-priming (in pathological conditions) of selfreactive
CD8 + T cells. This process may contribute
to the improved caspase-dependent immunogenicity
observed in some autoimmune or tumor models.
A major finding of this study is that in patients with
chronic HIV infection, apoptotic T cells seem to
induce a wide repertoire of effector (ef)CD8 + T cells
specific to apoptotic antigens in vivo. This is supported
by the evidence showing a correlation
between apoptosis and the strength of the efCD8 +
T-cell responses directed against the apoptosis-associated
peptides. The possible role of apoptotic epitope-specific
CD8 + T cells in AIDS immunopathology
is substantiated by the evidence that their magnitude
was related with the decline of circulating
CD4 + T cells, representing an accurate marker of
disease progression in HIV infection. The observation
that cross-presentation of apoptotic cells activate
efCD8 + T cells in HIV patients ex vivo, suggests
this mechanism might be operative in generating the
great variety of apoptotic antigen-specific CD8 + T
cells shown in these patients, as reported in several
experimental models.
In conclusion, it is tempting to envision from our
data that CIA commonly observed during different
chronic viral or autoimmune diseases results partly
from a vicious cycle. In that cycle, the cross-presen-
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tation of apoptotic T cells leads to the activation of
a large repertoire of apoptotic antigen-specific T
cells, which in turn undergo apoptosis after they
have performed their effector functions, and so on.
Depending on the amplification of this process, it
ultimately may contribute to the irreversible impairment
of the immune system, as in the case of HIV
infection. This knowledge may be exploited to tune
the immune homeostasis in diseases affected by
excessive T-cell apoptosis. Conversely, our recent
yet unpublished data suggest that the identification
of caspase-cleaved proteins from apoptotic tumor
cells may contribute to improve anti-tumor
immunotherapy in combination with efficient adjuvants,
appropriate chemotherapy, and even compounds
enhancing antigen cross-presentation via
inhibition of lysosomal acidification. Indeed, as documented
in our previous study (J Exp Med. 2005,
202:817-28,), efficient antigenic delivery for the
cross-presentation requires neutral pH in phagoendosomes,
in order that exogenous antigens are not
degraded in those compartments, and can thus
access the cytosolic processing pathway.
Selected publications
Rawson PM, Molette C, Videtta M, Altieri L,
Franceschini D, Donato T, Finocchi L, Propato A,
Paroli M, Meloni F, Mastroianni CM, d'Ettorre G,
Sidney J, Sette A, Barnaba V. Cross-presentation of
caspase-cleaved apoptotic self antigens in HIV infection.
Nat Med. 2007, 13:1431-9.
Meloni F, Accapezzato D, Agresti C, Aloisi F,
Ristori G, Salvetti M, Furlan R, Martino G, Barnaba
V, Paroli M. Dendritic cells loaded with apoptotic
oligodendrocytes as a source of myelin T-cell epitopes
in multiple sclerosis. Clin Immunol. 2008,
129:286-94.
Morandi F, Raffaghello L, Bianchi G, Meloni F,
Salis A, Millo E, Ferrone S, Barnaba V, Pistoia V.
Immunogenicity of human mesenchymal stem cells
in HLA-class I-restricted T-cell responses against
viral or tumor-associated antigens. Stem Cells 2008,
26:1275-87.