A naturally selected αβ T cell receptor binds HLA-DQ2 molecules without co-contacting the presented peptide 2025 Rossjohn et al

Abstract

αβ T cell receptors (TCR) co-recognise peptide (p) antigens that are presented by major histocompatibility complex (MHC) molecules. While marked variations in TCR-p-MHC docking topologies have been observed from structural studies, the co-recognition paradigm has held fast. Using HLA-DQ2.5-peptide tetramers, here we identify a TRAV12-1+-TRBV5-1+ G9 TCR from human peripheral blood that binds HLA-DQ2.5 in a peptide-agnostic manner.

The crystal structures of TCR-HLA-DQ2.5-peptide complexes show that the G9 TCR binds HLA-DQ2.5 in a reversed docking topology without contacting the peptide, with the TCR contacting the β1 region of HLA-DQ2.5 and distal from the peptide antigen binding cleft. High-throughput screening of HLA class I and II molecules finds the G9 TCR to be pan-HLA-DQ2 reactive, with leucine-55 of HLA-DQ2.5 being a key determinant underpinning G9 TCR specificity excluding other HLA-II allomorphs. Consistent with the functional assays, the interactions of the G9 TCR and HLA-DQ2.5 precludes CD4 binding, thereby impeding T cell activation.

Collectively, we describe a naturally selected αβTCR from human peripheral blood that deviates from the TCR-p-MHC co-recognition paradigm.

Open access

 

Interesting. HLADQ2.5 is a risk factor for coeliac, which seems to work differently foremother autoimmune disease in that we know the foreign T cell antigen, which is not the B cell auto antigen.

There also seems to be a weaker link to type I diabetes and lupus.

 

I don't know if you took a look at the text yet, but the T cell and HLA in this study were from a donor with coeliac. Which might support that this T cell might be relevant?

 

They may have been surprised because people have been working hard on identifying the gluten peptides that could be presented with DRQ2.5 in coeliac. If this paper's finding is relevant that answer would seem to be that it is not the fit of the gluten peptide that matters after all!

One way to invoke it might be say that DRQ2.5 might be capable of stimulating T cells without antigen and that might help along another T cell to recognise gluten when it should be anergia to foodstuffs. I have not read the full paper but maybe they theorise something like that.

 

It's all very technical for me, but they don't appear to speculate about disease mechanisms in the discussion, and they only ever mention coeliac in describing the donor.