Exposure to air pollutants induces oxidative stress. AhR recognizes polycyclic aromatic hydrocarbons on diesel exhaust particles (DEPs), promoting cytochrome P450 family 1 A1–mediated (CYP1A1-mediated) detoxification. Oxidative stress induces Nrf2 translocation to the nucleus, leading to antioxidant transcription. Failure to detoxify results in release of the neutrophil chemokine IL-8, the antigen-presenting cell (APC) chemokine CCL20, and proinflammatory cytokines (including IL-1, IL-6, and TNF-α) that in the absence of allergen promote naive T cell differentiation into IL-17A–producing Th17 cells. Similarly, exposure to mold-derived β-glucans, which signal through dectin-1, induces recruitment of IL-17A–secreting Th17 and γδT cells and neutrophils. Mold and other complex allergens also stimulate epithelial cells through pathogen-associated molecular pattern (PAMP) receptors like TLRs. TLR4 recognizes the house dust mite allergen Derp2 and endotoxins, which can modulate NF-κB activation of proinflammatory cytokines via the ubiquitin-modifying enzyme A20. Notch4-Jagged1 interaction between T cells and APCs, respectively, can induce Th2 cell generation when APCs are exposed to allergens and epithelial cell–derived IL-25, IL-33, and/or TSLP. These cytokines can be released following viral infection of epithelial cells and cellular damage resulting from exposure to pollutants and/or proteolytic allergens. They can induce innate lymphoid cells (ILC2s) to release IL-13, which drives mucus production and AHR, and IL-5, which is central to eosinophil biology. In addition to interacting with APCs and Th2 cells to potentiate allergic responses and IgE generation, ILC2s also release amphiregulin (AREG) to promote tissue repair. HRV and RSV infections in asthmatics can exacerbate Th2 responses and inhibit type 1 IFN responses, enhancing viral replication and promoting more severe disease.