DENND1B is a guanine nucleotide exchange factor (GEF) that activates RAB35 by promoting GDP-to-GTP exchange, converting it to its active form 1. In T helper 2 (TH2) cells, DENND1B regulates T-cell receptor (TCR) internalization through clathrin-mediated endocytosis via interaction with adapter protein complex 2 (AP-2), controlling the rate of TCR downmodulation and routing to endosomes 1. This process critically regulates cytokine production in TH2 lymphocytes 1. Beyond immune regulation, DENND1B localizes to cilia where it controls cilium length, function, and membrane composition through RAB35 regulation 2. DENND1B variants are strongly associated with asthma development; loss of DENND1B function results in delayed TCR downmodulation, enhanced TCR signaling, and increased effector cytokine production in TH2 cells, phenotypically consistent with hyper-allergic responses 1. Genome-wide association studies confirm DENND1B polymorphisms significantly associate with asthma, atopy markers, and severe asthma in diverse populations 3. Additionally, DENND1B variants link to obesity through melanocortin 4 receptor signaling and energy homeostasis regulation 4, and to narcolepsy type 1 through T-cell autoimmunity pathways 5. DENND1B also influences susceptibility to chr1 cavitary pulmonary aspergillosis 6.