Defining mast cell functions in effector T cell activation at the peripheral site of inflammation and the relevance of MHCII cross-dressing by dendritic cells

• Applicant: Professorin Dr. Anne Dudeck
• Subject Area: Immunology
• Term: since 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 431767831

Mast cells (MCs) are best known as effector cells of IgE-mediated type I allergic responses. However, there is increasing evidence for important MC functions in acute host defense and in the induction of adaptive responses. Using longitudinal intravital multiphoton microscopy, we recently found that skin inflammation results in a dynamic communication between MCs and dendritic cells (DCs), both tissue resident sentinel cells. DCs actively engulfed intact MC granules exocytosed by MC degranulation upon inflammatory insult. DCs bearing MC granules showed a highly enhanced maturation and migration to draining LNs, and a boosted T cell priming capacity. Conversely, before leaving the inflamed skin, DCs executed targeted and long-lasting interactions with MCs. These innate synapse-like contacts ultimately culminated in the transfer of protein material including MHC class II complexes to MCs thereby equipping MCs with antigen presentation capacity. Since MCs remain stationary at the site of inflammation, the "cross-dressing" of MCs with MHCII complexes by DCs may ensure the re-activation of effector T cells that home back to the skin. In the proposed project, we aim to identify the molecular mechanisms of the DC-to-MC communication and to decipher the functional consequence of MC education by DCs on MC functions. Moreover, we aim to determine how MCs contribute to the re-activation of effector T cells that have been primed in draining LN and home back to the inflamed skin, and in particular, the impact of MHCII complexes cross-dressed by DCs. Since MCs provide a broad spectrum of pro-inflammatory but also immunosuppressive mediators, antigen presentation to skin homing effector T cells by MCs may have a specific signature and result in distinct T cell polarization and cytokine response. Consequently, the extent of MC cross-dressing with MHCII complexes by DCs may correlate with distinct modulations of the amplitude and quality of T cell-driven inflammation. Therefore, modifying the communication between MCs and DCs may be a promising and innovative strategy to therapeutically intervene T cell-driven inflammatory diseases.

• DFG Programme: Research Grants