Non-classical MHC and Class 1-like molecules

Project Details

The major role of classical HLA-I molecules is to present peptides for recognition by CD8+ T cells. In contrast, the roles of non-classical class I molecules is more varied, often involving innate immunity. Perhaps the best characterised non-classical c lass I molecule is HLA-E (Qa-1b in mice) which is non-polymorphic and whose major role is to present leader peptides from other HLA-I molecules for recognition by CD94-NKG2 receptors expressed by NK and T cells (J Exp Med 187:813-18, J Immunol 162:305-313, J Immunol 188:302-10). In addition, both HLA-E and Qa-1b can present peptides for recognition by αβ TCR+ CD8+ T cells. Indeed we demonstrated that TCR recognition of HLA-E bound to a CMV-derived peptide resembled TCR recognition of classical HLA-I (Nature Immunol 7:256-64). Given the fact that this CMV-derived peptide is identical to a sequence found in many classical HLA-I molecules, we hypothesise that this particular response may impact transplant settings where CMV-reactivation is a major issue and have current studies in progress that address this issue.

More recently we have shown that non-classical MHC-I molecules can act as ligands for Ly49 receptors expressed by NK cells. Specifically we showed that Ly49A binds to H2-M3 and that this interaction impacts both on the acquisition of effector function by NK cells and their capacity to limit tumor growth (Nature Immunol 12:1171-77). Ongoing studies are aimed at determining the extent to which non-classical MHC molecules impact on NK and T cell activation.

Some viruses, in particular cytomegalovirus also encode proteins with an MHC-I-like fold that in the context of infection, typically have immune evasion functions. We have been studying the capacity of m157 a protein encoded by murine cytomegalovirus to interact with Ly49 receptors. Indeed, NK cell recognition of m157 is responsible for the control of acute viral replication in spleen and liver in mouse strains that possess the Ly49H receptor. We have recently shown that m157 binds this Ly49H in a way that is completely different how MHC-I proteins bind other Ly49 receptors. The class-I-like m157 binds to the stalk of Ly49H rather than the lectin-like domain, which contains the binding site for classical MHC-I proteins (Nature Immunol 14:699-705). This represents a rather novel strategy for immune evasion and we are currently furthering this work using additional functional and biochemical approaches.

Research Group

Brooks laboratory: Innate immunity; anti-viral immunity

Faculty Research Themes

Infection and Immunology

School Research Themes

Molecular Mechanisms of Disease

Key Contact

For further information about this research, please contact the research group leader.

Department / Centre

Microbiology and Immunology

MDHS Research library
Explore by researcher, school, project or topic.