A structural basis for CD8+ T cell-dependent recognition of non-homologous peptide ligands: implications for
Tatyana Sandalova1, Jakob Michaëlsson, Robert A Harris
1Department of Medical Biochemistry and Biophysics, Microbiology and Tumor Biology Center, and Strategic Research Center IRIS for Studies of Integrated Recognition in the Immune System, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Abstract:
Molecular mimicry of self-epitopes by viral antigens is one possible pathogenic mechanism underlying induction of autoimmunity. A self-epitope, mDBM, derived from mouse dopamine beta-mono-oxygenase (KALYDYAPI) sharing 44% sequence identity with the lymphocytic choriomeningitis virus-derived immunodominant epitope gp33 (KAVYNFATC/M), has previously been identified as a cross-reactive self-ligand, presentation of which results in autoimmunity. A rat peptide homologue, rDBM (KALYNYAPI, 56% identity to gp33), which displayed similar properties to mDBM, has also been identified. We herein report the crystal structure of H-2Db.rDBM and a comparison with the crystal structures of the cross-reactive H-2Db.gp33 and non-cross-reactive H-2Db.gp33 (V3L) escape variant (KALYNFATM, 88% identity to gp33). Despite the large sequence disparity, rDBM and gp33 peptides are presented in nearly identical manners by H-2Db, with a striking juxtaposition of the central sections of both peptides from residues p3 to p7. The structural similarity provides H-2Db in complex with either a virus-derived or a dopamine beta-mono-oxygenase-derived peptide with a shared antigenic identity that conserves the positioning of the heavy chain and peptide residues that interact with the T cell receptor (TCR). This stands in contrast to the structure of H-2Db.gp33 (V3L), in which a single conserved mutation, also present in rDBM, induces large movements of both the peptide backbone and the side chains that interact with the TCR. The TCR-interacting surfaces of the H-2Db.rDBM and H-2Db.gp33 major histocompatibility complexes are very similar with regard to shape, topology, and charge distribution, providing a structural basis for CD8 T cell activation by molecular mimicry and potential subsequent development of autoreactivity.
Insights
Molecular mimicry between viral and self-peptides, like gp33 and dopamine beta-mono-oxygenase (DBM), can trigger autoimmunity. Structural analysis reveals similar antigen presentation, explaining T cell activation and potential autoreactivity.
Area of Science:
- Immunology
- Structural Biology
- Molecular Mimicry
Background:
- Autoimmunity can arise from molecular mimicry, where viral antigens resemble self-epitopes.
- Dopamine beta-mono-oxygenase (DBM) derived self-epitopes share sequence identity with viral epitopes, such as lymphocytic choriomeningitis virus gp33.
- This cross-reactivity is implicated in the induction of autoimmune responses.
Purpose of the Study:
- To elucidate the structural basis of molecular mimicry between viral and self-peptides presented by H-2Db.
- To compare the crystal structures of H-2Db complexes with gp33, its escape variant (V3L), and the self-peptide rDBM.
- To understand how structural similarities and differences influence T cell receptor (TCR) interactions and autoreactivity.
Main Methods:
- X-ray crystallography was used to determine the structures of H-2Db.rDBM, H-2Db.gp33, and H-2Db.gp33 (V3L).
- Comparative structural analysis focused on peptide presentation, TCR-interacting surfaces, and conformational changes.
- Sequence identity and structural similarity metrics were employed.
Main Results:
- Despite sequence differences, rDBM and gp33 peptides are presented by H-2Db in nearly identical conformations, particularly at residues p3-p7.
- The TCR-interacting surfaces of H-2Db.rDBM and H-2Db.gp33 exhibit striking similarities in shape, topology, and charge.
- A single mutation in the gp33 (V3L) variant induces significant conformational changes in both the peptide and H-2Db, altering TCR interactions.
Conclusions:
- Structural similarities in H-2Db presentation of viral and self-peptides provide a shared antigenic identity, facilitating T cell activation.
- This molecular mimicry offers a structural explanation for CD8 T cell activation and the potential development of autoreactivity.
- Conformational plasticity in peptide presentation, influenced by mutations, can modulate autoimmune responses.
More Related Videos
Related Concept Videos
01:26Antigens Involved in Adaptive Immunity
Complete Antigens
Complete antigens possess both immunogenicity and reactivity.
01:22T Cell Activation and Clonal Selection
Naive T cells that have not yet encountered an antigen express two primary CD...
01:31Antigen Processing Pathways
MHC Class I: Presenting Endogenous...
01:28Diversity of Antigen Receptors
Before encountering any antigen, lymphocytes express these receptors. On B cells, the antigen receptor is a membrane-bound antibody molecule called BCR; on T cells, it is a T cell receptor or TCR. B and T cell receptors are composed of two...
00:42Cross-reactivity
01:24B Cell Activation and Differentiation
When naive B cells encounter a specific antigen that can bind to the B cell receptor (BCR) on their surface, they undergo sensitization to respond to the antigen's presence. Sensitization begins with...