Selection and Expansion of CD8α/α¹ T Cell Receptor α/β¹ 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/β¹ 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/β¹ 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/β¹ subsets has remained elusive. Using mutant mice lacking the expression of both H2-K^b and H2-D^b, we show that the CD8α/β¹TCR-α/β¹ subset is dependent on K or D molecules, whereas the CD8α/α¹TCR-α/β¹ subset is independent of classical MHC class I molecules. Furthermore, the CD8α/α¹ 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/β¹TCR-α/β¹ IELs are restricted by H-2K and H-2D molecules, whereas the unusual subset of CD8α/α¹TCR-α/β¹ resident IELs recognize nonclassical MHC class I–like molecules that are distinct from CD1.