Regulation of T Cell Receptor Signaling by DENND1B in TH2 Cells and Allergic Disease

The DENN domain is an evolutionary conserved protein module found in all eukaryotes and serves as an exchange factor for Rab-GTPases to regulate diverse cellular functions. Variants in DENND1B are associated with development of childhood asthma and other immune disorders. To understand how DENND1B may contribute to human disease, Dennd1b(-/-) mice were generated and exhibit hyper-allergic responses following antigen challenge. Dennd1b(-/-) T(H)2, but not other T-H cells, exhibit delayed receptor-induced T cell receptor (TCR) downmodulation, enhanced TCR signaling, and increased production of effector cytokines. As DENND1B interacts with AP-2 and Rab35, T(H)2 cells deficient in AP-2 or Rab35 also exhibit enhanced TCR-mediated effector functions. Moreover, human T(H)2 cells carrying asthma-associated DENND1B variants express less DENND1B and phenocopy Dennd1b(-/-) T(H)2 cells. These results provide a molecular basis for how DENND1B, a previously unrecognized regulator of TCR downmodulation in T(H)2 cells, contributes to asthma pathogenesis and how DENN-domaincontaining proteins may contribute to other human disorders.