Allergic airway inflammation (AAI) features airway and peribronchial accumulation of eosinophils and lymphocytes, which is a response to the cytokines interleukin (IL)-4, IL-5 and IL-13. Whereas T-helper type 2 (TH2) cells are clearly important for the development of AAI, it has been reported that natural killer T (NKT) cells1 and activated memory CD8+ T cells2 play essential effector roles in AAI. In contrast to earlier studies3, 4, Akbari et al. reported that NKT cell–deficient mice are resistant to allergic asthma and that transfer of NKT cells from wild-type animals to mice deficient in Jα281 (Jα281−/−)—a T-cell antigen receptor (TCR) gene segment used by NKT cells—restored the AAI response1. Further complexity in defining the nature of lymphocytes in AAI came from a recent study by Miyahara et al. demonstrating that CD8-deficient mice are resistant to AAI (ref. 2). Additionally, adoptive transfer of in vitro–activated CD8+ T cells with a memory phenotype restored AAI in these mice2. These results call into question the current paradigm that CD4+ T-helper cells are the main players in allergic asthma.

We undertook several approaches to examine the role of various T-cell populations in the development of AAI. Because T cells require molecules of the major histocompatibility complex (MHC) for their development and function, we used mice with genetic deletions in various regions of the MHC locus to delineate the role of NKT and CD8+ cells in AAI. The K and D regions of MHC encode molecules that are critical for the development of class Ia–restricted CD8+ T cells. Expression of class II molecules, on the other hand, is essential for the development and survival of CD4+ T cells and requires expression of the CIITA transcription factor. In addition, expression of class Ia and class I–like molecules, including class Ib and CD1d molecules, requires β2-microglobulin (β2m). CD1d allows the development of NKT cells, whereas other MHC class I–like molecules function as restriction elements for a unique CD8+ T-cell population with an intrinsically activated phenotype.