| First Author | Yang CW | Year | 2016 |
| Journal | Cell | Volume | 164 |
| Issue | 1-2 | Pages | 141-155 |
| PubMed ID | 26774822 | Mgi Jnum | J:229307 |
| Mgi Id | MGI:5751612 | Doi | 10.1016/j.cell.2015.11.052 |
| Citation | Yang CW, et al. (2016) Regulation of T Cell Receptor Signaling by DENND1B in TH2 Cells and Allergic Disease. Cell 164(1-2):141-55 |
| abstractText | 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(-/-) TH2, but not other TH 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, TH2 cells deficient in AP-2 or Rab35 also exhibit enhanced TCR-mediated effector functions. Moreover, human TH2 cells carrying asthma-associated DENND1B variants express less DENND1B and phenocopy Dennd1b(-/-) TH2 cells. These results provide a molecular basis for how DENND1B, a previously unrecognized regulator of TCR downmodulation in TH2 cells, contributes to asthma pathogenesis and how DENN-domain-containing proteins may contribute to other human disorders. |
