Persistence of apoptosis-resistant T cell-activating dendritic cells promotes T helper type-2 response and IgE antibody production

Abstract

Antigen-specific T cell-mediated apoptosis of dendritic cells (DCs) represents a unique down-regulatory mechanism that prevents the continuous activation of T cells by antigen-loaded DCs; this regulatory mechanism is impaired in allergy and as a consequence a large proportion of DCs tends to escape apoptosis following cognate interaction with CD4 + T cells. However, the biological relevance of greater numbers of apoptosis-resistant DCs to the development of allergic IgE-mediated reactions remained to be determined. Here, we sought to investigate the in vitro and in vivo regulatory features of apoptosis-resistant DCs and to assess their role in host sensitization. Freshly isolated CD11c +/hiB220 -DCs from ovalbumin (OVA)-sensitized, OVA-immunized and naïve Balb/c mice were cultured with OVA-specific T cells and levels of T cell-mediated DCs apoptosis assessed by flow cytometry. Surviving apoptosis-resistant DCs were then recovered and subsequently co-cultured with OVA-specific CD62L hiCD44 low naïve T cells or passively transferred into naive syngenic recipients. In vitro profile of DC and T cell lymphokine production, chemokine receptors expression and in vivo, post-adoptive DC transfer T helper (T H) and IgE responses were assessed. Apoptosis-resistant DCs showed differential regulatory properties compared to their freshly isolated counterpart independent of the sensitization status of the donor. When co-cultured with naïve OVA-specific T cells, apoptosis-resistant DCs from either sensitized or immunized mice induced T cells that produced increased levels of IL-4 and reduced levels of IFN-γ and showed increased expression of T H-2 related CCR4 and CCR8 chemokine receptors. Finally, adoptive transfer of apoptosis-resistant DCs, induced higher levels of OVA-specific IgE responses in absence of antigen challenge in syngenic recipients compared to freshly isolated DCs from both sensitized and immunized mice. These data would suggest that sensitization-associated increased numbers of apoptosis-resistant T cell-activating DCs contribute to the generation/maintenance of IgE-mediated allergic reactions.