Structural Basis for Unusual TCR CDR3β Usage Against an Immunodominant HIV-1 Gag Protein Peptide Restricted to an HLA-B*81:01 Molecule

Abstract

In HIV infection, some closely associated human leukocyte antigen (HLA) alleles are correlated with distinct clinical outcomes although presenting the same HIV epitopes. The mechanism that underpins this observation is still unknown, but may be due to the essential features of HLA alleles or T cell receptors (TCR). In this study, we investigate how T18A TCR, which is beneficial for a long-term control of HIV in clinic, recognizes immunodominant Gag epitope TL9 (TPQDLTML180-188) from HIV in the context of the antigen presenting molecule HLA-B*81:01. We found that T18A TCR exhibits differential recognition for TL9 restricted by HLA-B*81:01. Furthermore, via structural and biophysical approaches, we observed that TL9 complexes with HLA-B*81:01 undergoes no conformational change after TCR engagement. Remarkably, the CDR3β in T18A complexes does not contact with TL9 at all but with intensive contacts to HLA-B*81:01. The binding kinetic data of T18A TCR revealed that this TCR can recognize TL9 epitope and several mutant versions, which might explain the correlation of T18A TCR with better clinic outcomes despite the relative high mutation rate of HIV. Collectively, we provided a portrait of how CD8+ T cells engage in HIV-mediated T cell response.

Structural basis of the TCR-pHLA complex provides insights into the unconventional recognition of CDR3β in TCR cross-reactivity and alloreactivity

“…Interestingly, most TCRs used CDR3α and CDR3β to accommodate the various epitopes, but the role of CDR3β was different in the TCR T18A/B4201/TL9 complex. This unusual TCR CDR3β usage was observed previously in TCR T18A/B8101/TL9 complex we reported (PDB: 7DZM )( Liu et al., 2022 ). To conclude, the structural determination of this study revealed that TCR T18A adopts essentially identical conformation at the peptide-MHC interface across B∗42:01 and B∗81:01 restriction.…”

“…To critically examine why T18A TCR can creatively bind to distinct antigen-presenting surfaces in different HLA contexts, we previously obtained the structure of T18A and TPQDLNTML in the B∗81:01 complex (PDB: 7DZM )( Liu et al., 2022 ) and determined the structure of T18A and TPQDLNTML in B∗42:01 complex in this study. The statistics of the T18A TCR/B42/TL9 crystals were described ( Table S1 ), and the structures of the ternary complexes were shown ( Fig.…”

“…Binding capacity of T18A TCR to different p -MHC molecules were measured by in vitro surface plasmon resonance (SPR). We previously reported that T18A could recognize the TL9 peptide presented by B∗81:01 with a high affinity (K D ~ 4.7 μM), and could effectively recognize some escape variants of TL9, such as 7s-TL9 (K D ~ 31.4 μM)( Liu et al., 2022 ). Similarly, T18A was able to recognize TL9 peptides presented by B∗42:01 with moderate affinity (Kd ​~ ​46.1 ​μM), as well as 7s-TL9 (K D ~ 51.4 μM) ( Fig.…”

“…Interestingly, HIV-1 sequence analysis based on HIV-1 infected patients( Currier et al., 2006 ; Dorrell et al., 2001 ; Kløverpris et al., 2012 , 2015c ; Payne et al., 2014 ) showed that the mutation frequency of TL9 epitope in the B∗81:01 expressing individuals was significantly higher than that in the B∗42:01 expressing individuals and the cohort without the above two alleles ( Table S4 ). We previously showed that under the background HLA-B∗81:01, the TL9 epitope preferred mutations were 3s-TL9 and 7s-TL9( Liu et al., 2022 ). In this study, we found in the context of HLA B∗42:01, the mutations in the TL9 epitope focus on position 3, and the most preferred mutation was 3t-TL9 ( Fig.…”

A structure-guided approach to predict MHC-I restriction of T cell receptors for public antigens

“…While the exact model for MHC restriction of TCR recognition has been debated (reviewed in ref. 13 ), it is clear that TCRs can be alloreactive i.e., recognize the same peptide antigen in the context of different HLA allotypes [13][14][15][16][17][18][19][20] . A notable example is the LC13 TCR that reacts with peptide-bound HLA-B*08:01 and HLA-B*44:05 15 .…”