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.
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