Selection and expansion of CD8α/α⁺ T cell receptor α/β⁺ intestinal intraepithelial lymphocytes in the absence of both classical major histocompatibility complex class I and nonclassical CD1 molecules

Intestinal intraepithelial lymphocytes (IELs) in mice include two main subsets of TCR-α/β⁺ cells which differ functionally and ontogenically from each other. One expresses the CD8α/α homodimer, whereas the other expresses the CD8α/β heterodimer. Although the presence of all CD8⁺TCR-α/β⁺ IELs is dependent on β2-microglobulin molecules, the nature of the major histocompatibility complex (MHC) class I molecules recognized by the CD8α/α and the CD8α/β⁺ subsets has remained elusive. Using mutant mice lacking the expression of both H2K^b and H2-D^b, we show that the CD8α/β⁺TCR- α/β⁺ subset is dependent on K or D molecules, whereas the CD8α/α⁺TCR- α/β⁺ subset is independent of classical MHC class I molecules. Furthermore, the CD8α/α⁺ cells are conserved in mice lacking expression of CD1, a nonclassical MHC class I-like molecule previously proposed to be a potential ligand for IELs. Using transporter associated with antigen processing (TAP)-deficient mice, this cell population can be further separated into a TAP-dependent and a TAP-independent subset, suggesting either the recognition of two nonclassical MHC-like molecules, only one of which is TAP dependent, or the involvement of a single nonclassical MHC-like molecule that is only partially TAP dependent. These findings demonstrate that CD8α/β⁺TCR-α/β⁺ IELs are restricted by H-2K and H-2D molecules, whereas the unusual subset of CD8α/α⁺TCR-α/β⁺ resident IELs recognize nonclassical MHC class I-like molecules that are distinct from CD1.