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Large scale characterization of the LC13 TCR and HLA-B8 structural landscape in reaction to 172 altered peptide ligands: a molecular dynamics simulation study.

ABSTRACT: The interplay between T cell receptors (TCRs) and peptides bound by major histocompatibility complexes (MHCs) is one of the most important interactions in the adaptive immune system. Several previous studies have computationally investigated their structural dynamics. On the basis of these simulations several structural and dynamical properties have been proposed as effectors of the immunogenicity. Here we present the results of a large scale Molecular Dynamics simulation study consisting of 100 ns simulations of 172 different complexes. These complexes consisted of all possible point mutations of the Epstein Barr Virus peptide FLRGRAYGL bound by HLA-B*08:01 and presented to the LC13 TCR. We compare the results of these 172 structural simulations with experimental immunogenicity data. We found that simulations with more immunogenic peptides and those with less immunogenic peptides are in fact highly similar and on average only minor differences in the hydrogen binding footprints, interface distances, and the relative orientation between the TCR chains are present. Thus our large scale data analysis shows that many previously suggested dynamical and structural properties of the TCR/peptide/MHC interface are unlikely to be conserved causal factors for peptide immunogenicity.

SUBMITTER: Knapp B

PROVIDER: S-EPMC4125040 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Large scale characterization of the LC13 TCR and HLA-B8 structural landscape in reaction to 172 altered peptide ligands: a molecular dynamics simulation study.

Knapp Bernhard B Dunbar James J Deane Charlotte M CM

PLoS computational biology 20140807 8

The interplay between T cell receptors (TCRs) and peptides bound by major histocompatibility complexes (MHCs) is one of the most important interactions in the adaptive immune system. Several previous studies have computationally investigated their structural dynamics. On the basis of these simulations several structural and dynamical properties have been proposed as effectors of the immunogenicity. Here we present the results of a large scale Molecular Dynamics simulation study consisting of 100 ...[more]

PMID: 25101830

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Project description:BackgroundRecent reports have suggested that Common Variable Immunodeficieny (CVID) can present as an autosomal dominant trait dependent on the inheritance of a set of uncommon mutations/alleles of TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) involving exons 3 or 4. Penetrance, however, appears to be incomplete. Among our clinic population, the greatest genetic linkage for CVID is to the major histocompatibility complex (MHC) on chromosome 6. The majority of our patients have inherited HLA *DQ2, *DR7, *DR3(17), *B8, and/or *B44. Of these, HLA*B44 was present in almost half of the patients and was thus the most common susceptibility allele. HLA *B44 was also found to be over-represented among patients who presented to our clinic with adult-onset recurrent sinopulmonary infections (RESPI) and normal serum immunoglobulin levels, a cohort that included first and second degree relatives of patients with CVID. One of the two original reports of the association between TACI and CVID also reported Human Leukocyte Antigen (HLA) haplotypes. Of 13 affected subjects, nine had inherited HLA *B8 and six had inherited HLA B44. This raised the possibility that TACI mutations might synergize with MHC class I alleles to enhance susceptibility to humoral immune deficiency.MethodsWe identified 63 CVID patients irrespective of HLA status and 13 RESPI patients who had inherited HLA*B44. To evaluate for mutations in the gene for TACI, we PCR amplified and sequenced TACI exons 3 and 4 from these patients.ResultsOf the 76 patients, eleven proved heterozygous for a previously reported, silent T->G polymorphism [rs35062843] at proline 97 in exon 3. However, none of the 13 RESPI patients and only one of the 63 CVID patients inherited a TACI allele previously associated with CVID. This patient was heterozygous for the TACI A181E allele (exon 4). She did not carry *DQ2, *DR7, *DR3(17), *B8, or *B44.ConclusionThese findings suggest that TACI mutations are unlikely to play a critical role in creating susceptibility to CVID among patients with previously recognized MHC class I and class II susceptibility alleles. Supported by NIH/USIDNET N01-AI30070, NIH R21 AI079741 and NIH M01-RR00032.

Project description:Recruitment and activation of CD8 T cells occur through specific triggering of T cell receptor (TCR) by peptide-bound human leucocyte antigen (HLA) ligands. Within the generated trimeric TCR-peptide:HLA complex, the molecular binding affinities between peptide and HLA, and between TCR and peptide:HLA both impact T cell functional outcomes. However, how their individual and combined effects modulate immunogenicity and overall T cell responsiveness has not been investigated systematically. Here, we established two panels of human tumor peptide variants differing in their affinity to HLA. For precise characterization, we developed the "blue peptide assay", an upgraded cell-based approach to measure the peptide:HLA affinity. These peptide variants were then used to investigate the cross-reactivity of tumor antigen-specific CD8 T cell clonotypes derived from blood of cancer patients after vaccination with either the native or an affinity-optimized Melan-A/MART-1 epitope, or isolated from tumor infiltrated lymph nodes (TILNs). Vaccines containing the native tumor epitope generated T cells with better functionality, and superior cross-reactivity against potential low affinity escape epitopes, as compared to T cells induced by vaccines containing an HLA affinity-optimized epitope. Comparatively, Melan-A/MART-1-specific TILN cells displayed functional and cross-reactive profiles that were heterogeneous and clonotype-dependent. Finally, we took advantage of a collection of T cells expressing affinity-optimized NY-ESO-1-specific TCRs to interrogate the individual and combined impact of peptide:HLA and TCR-pHLA affinities on overall CD8 T cell responses. We found profound and distinct effects of both biophysical parameters, with additive contributions and absence of hierarchical dominance. Altogether, the biological impact of peptide:HLA and TCR-pHLA affinities on T cell responses was carefully dissected in two antigenic systems, frequently targeted in human cancer immunotherapy. Our technology and stepwise comparison open new insights into the rational design and selection of vaccine-associated tumor-specific epitopes and highlight the functional and cross-reactivity profiles that endow T cells with best tumor control capacity.

Dataset Information

Large scale characterization of the LC13 TCR and HLA-B8 structural landscape in reaction to 172 altered peptide ligands: a molecular dynamics simulation study.

Publications

Large scale characterization of the LC13 TCR and HLA-B8 structural landscape in reaction to 172 altered peptide ligands: a molecular dynamics simulation study.

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