CD8 is a coreceptor of T cells for the recognition of peptide–MHC (pMHC) on antigen-presenting cells. It exists in two forms: an αα homodimer and an αβ heterodimer. The different functions of these two forms have long been a mystery, although it is believed that the heterodimer has a stronger affinity than the homodimer for pMHC. The structural basis of the interaction between pMHC and the αα homodimer in humans and mice was determined by X-ray crystallography a few years ago, but no structural explanation for the functional differences between homo- and heterodimers could be deduced. Two recent papers provide some clues on this matter.In their investigation of the functional consequences of carbohydrate changes associated with T-cell differentiation in the thymus, Moody et al. [1xDevelopmentally regulated glycosylation of the CD8αβ coreceptor stalk modulates ligand binding. Moody, A.M et al. Cell. 2001; 107: 501–512Abstract | Full Text | Full Text PDF | PubMed | Scopus (152)See all References][1] show that it is the β-chain of CD8 that modulates the binding of the Ig-like domain of the αβ heterodimer head to pMHC through the (O-linked) glycans on its stalk region, in such a way as to reorient the heterodimer towards pMHC. The O-glycosylation is highly programmed during T-cell development and controlled by ST3Gal-l sialyltransferase in the CD8 stalk region, which is highly glycosylated in both the homo- and heterodimeric forms of CD8.In contrast to the unique function of the β-chain in modulating the pMHC-binding avidity of the αβ heterodimer, Leishman et al. [2xT-cell responses modulated through interaction between CD8αα and the nonclassical MHC class I molecule, TL. Leishman, A.J et al. Science. 2001; 294: 1936–1939Crossref | PubMed | Scopus (174)See all References][2] show that the αα homodimer (not αβ heterodimer) in intestinal intraepithelial T lymphocytes (iIELs) mediates the activation of iIELs upon binding to TL antigen, an MHC-related molecule expressed on the surface of intestinal epithelial cells. This makes CD8αα a modulator of T-cell activation, in addition to its known function as a coreceptor. As well as cell-based experiments, the authors used BIAcoretm analysis to confirm this interaction. TL antigen binds to αα homodimer preferentially with a much higher affinity than it binds to αβ heterodimer. The affinity between TL and CD8αα is in the range of the T-cell receptor–pMHC interaction, much greater than the affinity of the interaction between CD8αα and pMHC, whereas the binding of TL to CDαβ is almost undetectable.These two papers provide compelling evidence that the CD8αα homodimer and CD8αβ heterodimer are truly different in their functions, at least in mice. It is noteworthy that a TL homologue has not been found in humans, and so the question remains as to whether these findings apply to human CD8.