download report - Istituto Pasteur

P a r t i c i p a n t s :
Marino Paroli, professor; Daniele Accapezzato, researcher;
Vittorio Francavilla, Pisana Moroni, Antonella Propato,
post-doc fellows; Melissa Videtta, Tiziana Donato, Debora
Franceschini, Francesca Meloni, Laura Altieri, PhD students.
Report of activity
The capacity of professional antigen-presenting
cells (pAPCs) to present either exogenous antigens
derived from other cells (usually necrotic or apoptotic
cells), or soluble antigens on class I molecules
to CD8 + T cells is defined as cross-presentation.
This process is primarily carried out by dendritic
cells (DCs) in vivo, and seems to be crucial for inducing
both CD8 + T cell immunity (cross-priming)
against allografts, tumors, or those pathogens that do
not infect or impair pAPCs, and tolerance (cross-tolerance)
against self-antigens. An additional support
for the idea that DCs carry out opposing functions
according to their maturational stage and the
microenvironment in which they work is provided by
studies investigating the complex interplay amongst
cross-presentation, apoptotic cells, DCs and stimulatory
signals. The current view suggests that, under
steady state conditions, apoptotic cells are consistently
captured by immature DCs that in turn induce
tolerance (or cross-tolerance) of apoptotic cellderived
antigen-specific T cells. Otherwise, DCs
mature and cross-prime these T cells in the presence
of sustained infectious/inflammatory mediators,
necrotic cell products, or CD4 + Th cells inducing
DC maturation via the CD40/CD40L interaction. In
this project, we have studied more in depth the consequences
of cross-presentation of apoptotic cells
unveiling self-antigens during the course of inflammatory
processes. In addition, we investigated the
possibility to exploit this phenomenon in order to
identify new self- or tumor-associated antigens that
could be included for the design of innovative strate-
Principal investigator: Vincenzo Barnaba
Professor of Internal Medicine
Dipartimento di Medicina Interna
Tel: (+39) 06 4453994; Fax: (+39) 06 49383333
vincenzo.barnaba@uniroma1.it
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Cellular and molecular immunology - AREA 5
Innovative strategies eliciting CD8 T cell responses by exploiting
proteomic analysis and improving cross-presentation
gies for the manipulation of immune responses in the
related diseases.
Principal results and perspectives
As demonstrated by our previous data (Nature Med.
2001, 7:807-13), apoptotic CD40L + T cells directly
induce DC maturation and cross-priming of CD8 + T
cells specific to apoptotic cell-associated self-antigens,
irrespective of additional exogenous signals. In contrast,
if apoptotic T cells are CD40L - (such as those
derived from resting T cells), the help of a third party
activated T cell or surrogate CD40L molecule is
needed for priming. Thus, the balance between
CD40L + (apoptotic) and CD40L - T cells during
cross-presentation appears to dictate tolerance or
induction of CD8 T cell responses against T cellassociated
epitopes, and to maintain or to stop the
related responses in the course of an inflammatory
process. It is tempting to hypothesize that these
responses have a critical role in the amplification of
chronic inflammation via the continuous bystander
effects of inflammatory cytokines produced by T cells
specific for the apoptotic T cell-associated antigens.
In this context, more recently we studied the intricate
interplay amongst apoptotic cells, cross-presentation
and the phenomenon of chronic immune activation
(CIA). CIA is hallmark of several chronic
immune-mediated (viral or autoimmune) diseases. It
is characterized by: (a) hyper-reactivity of T and B
cells resulting in (b) a continuous turnover of apoptotic
cells derived from the former, and (c) hyper-production
of cytokines and chemokines. It is only in
minimal part due to self-antigen or virus-specific T
cells, as only a small proportion of activated T cells
are specific for the viruses or the self antigens related
to the relevant diseases. The origin of CIA is not
clear and has been attributed to various causes,
including bystander T cell activation, homeostatic
proliferation, T cell responses to a variety of selfantigens
or gut microorganisms, progressive loss of
regulatory T cells.