Week 7: HLA & peptides

This week I read a lot of interesting literature to inform my project. Below is my interpretation of the three most relevant papers I read. With HLA imputation in hand from last week and structural analysis coming next, I wanted to understand what it means to say an HLA allele confers risk, since the allele only matters through which peptides its binding groove will hold and which T cells will recognize them.

The first was Reynisson et al. in Nucleic Acids Research on NetMHCpan-4.1 and NetMHCIIpan-4.0, pan-specific neural networks that predict peptide binding to MHC class I and class II from the MHC sequence, trained on a mix of binding affinity and mass-spec eluted ligand data, and covering more than eleven thousand class I alleles and close to a thousand class II alleles. This changed how I think about testing an HLA association. I had been treating an HLA allele as a categorical label, where a patient either carries DQB1*06:02 or does not, and the predictor reframes the allele as a function from peptide sequences to binding scores, which means two carriers are equivalent at the allele level but differ in which self-peptide reaches a T cell depending on the proteome they happen to be exposing. The class II coverage matters for me since most of my endocrine candidates are DQ and DP alleles, and the ability to combine alpha and beta chains is what makes a DQA1/DQB1 or DPA1/DPB1 association interpretable at the peptide level at all.

The second was Siebold et al. in PNAS, the crystal structure of HLA-DQ0602 (DQA1*01:02/DQB1*06:02), the same molecule strongly associated with narcolepsy and dominantly protective against type 1 diabetes. Structural comparisons with closely related DQ molecules showed that the P4 pocket volume drives the narcolepsy susceptibility while the P6 and P9 pockets determine the breadth of peptides bound in the protective context. Reading this shifted how I think about the same allele showing up in the hypophysitis literature, since the relevant question moves from whether DQB1*06:02 associates with toxicity to which pocket geometry is doing the work and which self-peptide that pocket can hold. It also makes close-relative comparisons more important than I had thought, since DQB1*06:01 and DQB1*06:02 differ at only a few residues, and the residues that distinguish a risk allele from a protective one are where the mechanism lives.

The third was Prinz in Frontiers in Immunology, a review of the methodological problems with identifying which self-peptides drive autoimmune T-cell responses, given that class II molecules can present peptides from both extracellular and cellular self-proteins and TCRs are polyspecific. This reframed how confident I should be about any mechanistic story I attach to an HLA association. I had been picturing the chain from allele to peptide to T cell as something I could in principle write down for a given hit, and the review makes clear that the immunopeptidome of a class II allele is enormous, that polyspecific TCRs blur which peptide is the relevant one, and that for most HLA-associated autoimmune diseases the driving self-peptide remains unknown despite decades of work. It is a useful check on the temptation to over-narrate from an association, and it gives me a more honest sense of what a structural analysis can and cannot resolve about why a given allele predisposes to a given toxicity.