Chronic Inflammation in Asthma: Looking Beyond the Th2 Cell

Asthma is a common chronic inflammatory disease of the airways. A substantial number of patients present with severe and therapy-resistant asthma, for which the underlying biological mechanisms remain poorly understood. In most asthma patients, airway inflammation is characterized by chronic activation of type 2 immunity. CD4⁺ T helper 2 (Th2) cells are the canonical producers of the cytokines that fuel type 2 inflammation: interleukin (IL)-4, IL-5, IL-9, and IL-13. However, more recent findings have shown that other lymphocyte subsets, in particular group 2 innate lymphoid cells (ILC2s) and type 2 CD8⁺ cytotoxic T (Tc2) cells, can also produce large amounts of type 2 cytokines. Importantly, a substantial number of severe therapy-resistant asthma patients present with chronic type 2 inflammation, despite the high sensitivity of Th2 cells for suppression by corticosteroids-the mainstay drugs for asthma. Emerging evidence indicates that ILC2s and Tc2 cells are more abundant in severe asthma patients and can adopt corticosteroid-resistance states. Moreover, many severe asthma patients do not present with overt type 2 airway inflammation, implicating non-type 2 immunity as a driver of disease. In this review, we will discuss asthma pathophysiology and focus on the roles played by ILC2s, Tc2 cells, and non-type 2 lymphocytes, placing special emphasis on severe disease forms.