HDM and mannose as novel tolerogenic inducers for dendritic cells: mTOR/PPARγ-mediated attenuation of allergic asthma.

Dendritic cells (DCs) are pivotal in balancing immunity and tolerance in allergic asthma. This study reveals that both house dust mite (HDM) and mannose induce a potent tolerogenic phenotype in bone marrow derived DCs (BMDCs). These DCs display hallmark tolerogenic features, including a reduced proportion of DC-SIGN⁺ cells, downregulation of co-stimulatory molecules (MHC-II, CD80, and CD86) and key Th2-promoting factors (Jagged-1, OX40L), coupled with impaired phagocytosis and a reduced capacity to stimulate naïve CD4(+) T cell proliferation. Crucially, HDM- and mannose-induced DCs effectively promoted the differentiation of naïve CD4(+) T cells into Foxp3(+) regulatory T (Treg) cells, demonstrating their direct role in actively enforcing immune tolerance. Adoptive transfer of these tolerogenic DCs significantly alleviated airway inflammation in a murine asthma model. Mechanistically, we identified a novel metabolic checkpoint that involves HDM-mediated activation of mTOR/PPARγ signaling. Inhibition of mTOR disrupted this axis and reversed the tolerogenic state, while pharmacological activation of PPARγ with pioglitazone mitigated asthma pathology in vivo. In conclusion, our work establishes HDM and mannose as novel tolerogenic inducers, providing a new strategy for the immunotherapy of asthma.