7,25 The recognition
of cells by the immune system when undergoing redox stress is not well see more defined. Our data suggest that cells undergoing a redox stress that leads to a lowering in the levels of intracellular glutathione may begin to display MHC class I dimers on their cell surface. Such alterations in cellular glutathione levels have been reported to occur during T-cell activation26,27 and also during apoptosis.17,18,28 A more extensive study monitoring both MHC class I dimer formation and the level of glutathione in cells undergoing a variety of stimuli would, we consider, be of some worth. Furthermore, distinguishing whether both apoptotic and necrotic cell death pathways induce dimers would also be informative, alongside other pathological states such as viral infection, Fulvestrant purchase and many others that induce inflammatory responses and the production of reactive oxygen species. This would allow a pattern of conditions to be catalogued under which MHC class I dimer formation is induced. Although various MHC class I dimers have been reported in the literature, their potential biological role remains enigmatic.8,13 Of significant note, however, are the observations that Ig-MHC class I dimers can act to tolerize T cells.29 In this study, Kourilsky and colleagues used a soluble H2-Kd molecule dimerized with a cross-linking antibody to demonstrate
that an antigen-specific T-cell hybridoma was initially activated, followed by a state of unresponsiveness. It has also been demonstrated that antigen-specific occupancy of just one of the two peptide-binding grooves in an
Thymidylate synthase MHC class I dimer can have an effect on T cells,30 which may allow not only the HLA-B dimers we show here, but also the HLA-A-B dimers we describe in Fig. 2 to have some biological activity. Hence, the MHC class I dimers detected on apoptotic cells, and also on exosomes,15 may be capable of providing signal, including tolerogenic signals to immune cells. Similarly, tumour cells undergoing apoptosis, or releasing exosomes containing tumour-associated or tumour-specific antigens may influence T-cell behaviour. Of further interest is the possible recognition of MHC class I dimers by members of the NK cell receptor family. It has been shown that a disulphide-linked engineered version of the KIR2DL1 receptor has an increased affinity for HLA-C,31 and that KIR molecules can form an array of dimers and multimers in a zinc-dependent interaction.32 Hence interactions between dimers of both ligands and receptors may occur, potentially inducing extra stability for the generation of either inhibitory or activatory signals. As indicated above, defining the various conditions under which such dimers form would allow the design of experiments to directly study their potential influence on immune responses.