Five decades since the first description of an HLA association with disease, the HLA molecule has been demonstrated to be central to physiology, protective immunity and deleterious immune reactivity.
The specificity of HLA–peptide–T cell receptor (TCR) tripartite interactions is fundamental in enabling the adaptive immune system to mount an efficient and appropriate response to counteract infection and malignancy while maintaining self tolerance and preventing autoimmune disease.
Understanding the molecular principles that govern these interactions — so as to distil them into mechanistic insight regarding the role of HLA in driving and protecting against immunopathology — presents an ongoing biomedical research challenge but also holds much therapeutic promise.
The molecular mechanisms identified to date that influence HLA–peptide–TCR interactions and that have been implicated in autoimmune disease development include alternate TCR docking, low-affinity-mediated thymic escape, TCR stabilization of weak peptide–HLA complexes, altered binding registers, 'hotspot' molecular mimicry, post-translational modification of antigenic peptides, hybrid peptides and differential HLA expression and stability.
The identification of these numerous molecular mechanisms represents the outcome of several key technological advances in genetics, genomics, statistics, computational biology, peptide–HLA tetramer use for T cell repertoire interrogation and epitope mapping, structural biology and transgenics.
The progress in characterizing HLA diversity, HLA associations with human disease and HLA–peptide–receptor interactions and their mechanistic implications has galvanized efforts to harness the improved understanding of HLA function for clinical benefit, leading to the development and trialling of antigen-specific therapies that include vaccination and a range of other noncellular disease prevention strategies and therapies as well as cell-based therapeutic approaches.
Fifty years since the first description of an association between HLA and human disease, HLA molecules have proven to be central to physiology, protective immunity and deleterious, disease-causing autoimmune reactivity. Technological advances have enabled pivotal progress in the determination of the molecular mechanisms that underpin the association between HLA genetics and functional outcome. Here, we review our current understanding of HLA molecules as the fundamental platform for immune surveillance and responsiveness in health and disease. We evaluate the scope for personalized antigen-specific disease prevention, whereby harnessing HLA–ligand interactions for clinical benefit is becoming a realistic prospect.
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C.A.D. is supported by the Wellcome Centre and the Royal Society. J.R. is supported by grants from the National Health and Medical Research Council (Australia), the Cancer Council of Victoria, the Australian Research Council (ARC) and Worldwide Cancer Research and is an ARC Laureate Fellow. L.F. is supported by the Wellcome Centre, the Medical Research Council, the Danish National Research Foundation, Takeda and the Oak Foundation.
The authors declare no competing financial interests.
- Linkage disequilibrium
The nonrandom association of alleles at different loci, for example, owing to close physical proximity within a genomic region.
- Gene conversion
The process by which one allele is converted to another by mismatch repair mechanisms.
- Heterozygote advantage
The increased relative fitness of an organism conferred by having two different forms of a genetic variant, as opposed to having two identical copies of either of the two forms.
- Frequency-dependent selection
An evolutionary process whereby fitness of a given phenotype depends on its frequency relative to other phenotypes in a study population. Positive selection will occur if the fitness of the phenotype increases as its frequency increases, whereas negative selection will occur if the fitness decreases as the frequency of the phenotype increases.
- HLA restriction
A property of T cells whereby a given T cell receptor will recognize and respond to an antigen only when it is presented by a particular HLA molecule.
Non-germline-encoded (and thus non-inherited) antigens that may arise because of somatic mutation (as in cancer) or other processes such as post-translational modification and splicing together of peptides.
- Pancreatic islets
Clusters of different cell types found throughout the pancreas that include the insulin-producing β-cells, which are a main target of the autoimmune response occurring in patients with type 1 diabetes.
Different MHC protein forms encoded by different alleles.
- Unfolded protein response
A cellular stress response triggered because of the accumulation of unfolded or misfolded proteins within the endoplasmic reticulum.
- Epitope spreading
Describes how a self-directed immune response induced by a single peptide (or epitope) could spread to include other peptides (or epitopes), not only on the same autoantigen (intramolecular spreading) but also on other self molecules in close vicinity to the target cell (intermolecular spreading).
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