Role de l'ADN endogène et d'Interferon Response Factor-3 dans l'induction des réponses immunitaires médiées par les lymphocytes T auxiliaires de type 2.

Adaptative type 2 helper T cell (Th2) responses represent an important component of
adaptative immunity and are implicated in various (patho)physiological processes such as
allergic diseases, host defense against helminths and artificially adjuvanted vaccination.
Induction of adaptative T responses occurs with the help of innate immune cells,
especially dendritic cells (DCs). These DCs make the link between innate and adaptative
immunity by taking up antigens in peripheral tissues, migrating to lymphoïd organs and
presenting antigens to T lymphocytes. Direct or indirect activation of these cells depends on
the interaction between exogenous or endogenous danger signals and conserved innate
immune receptors, mainly represented by Pattern Recognition Receptors (PRRs). Despite
the importance of Th2 responses, the innate immune mechanisms leading to their activation
remain partially unknown. For this reason, we have been interested in immune mechanisms
underlying the induction of Th2 responses in two major Th2-dependent immunological
processes : airway allergy and vaccination with aluminium hydroxides (alum).
Airway allergy, of which the most severe manifestation is allergic ashma, is a
constantly increasing disease in developped countries. It appears clearly that the stimulation
of PRRs by allergens or immunostimulatory molecules plays a key role in the
pathophysiology of airway allergy. In addition, PRRs transduce the signal though a limited
number of signaling pathways and the role of Interferon Response Factor (IRF)-3 and
IRF-7, two important transcription factors downstream of various PRRs, in the
pathogenesis of allergic asthma, remains unknown. Therefore, we have investigated their
potentiel implication in this disease. We have discovered that IRF-3, but not IRF-7, plays an
essential role in allergic airway sensitization against house dust mite antigens, the main
allergen source in humans. We have further demonstrated that IRF-3 was intrinsically
required in lung DCs for their proallergic function. The IRF-3-dependent effects were
independent of type I interferons, the main target genes of IRF-3.
Alum is the most widely used artificial adjuvant in human and animal vaccination.
Yet, little is known about its mechanism of action, in particular regarding the nature of
signals and signaling pathways promoting Th2 responses. We have postulated that alum,
like any other efficient adjuvant, must be expected to stimulate innate immunity. On one hand, alum does not contain any molecular pattern that is recognized by PRRs and, on the
other hand, alum is known to be cytotoxic. Therefore, we hypothetised that alum-induced
endogenous danger signals could play a role in its adjuvant activity. Here, we report that
alum induces cell death and subsequent DNA release. This DNA acts as a endogenous
immunostimulatory signal relaying alum adjuvant activity on adaptative responses.
Furthermore, we propose that host DNA differentially regulates IgG1 and IgE production
following alum immunization. Indeed, an IRF-3-dependent DNA signaling pathway plays a
role in the activation of inflammatory DCs, the subsequent induction of Th2 response and
IgE isotype switching, whereas DNA also induces IgG1 production through IRF-3-
independent mechanisms. The finding that host cell endogenous DNA is a damageassociated
molecular pattern relaying alum adjuvant activity may thus help in the
comprehension of the mechanisms of action of current vaccines and in the design of novel
adjuvants.
In conclusion, this work has identified a previously unappreciated role for IRF-3, a
transcription factor downstream of various PRRs primarily implicated in antiviral
responses, in two Th2-dependent immunological processes: allergic asthma and alum-based
vaccination. In these models, we have shown that IRF-3 was intrinsically required in
professional antigen presenting cells, namely DCs, in order to activate them, a precondition
for the priming of adaptative Th2 responses. In addition, we also discovered that host DNA
released upon alum treatment acts as an endogenous danger signal mediating the adjuvant
activity of alum.