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Major histocompatibility complex determinants select T-cell receptor alpha chain variable region dominance in a
K Natarajan1, D Burstyn, M Zauderer
1Cancer Center, University of Rochester School of Medicine, NY 14642.
Summary
Dominant T-cell receptor (TCR) gene expression can be MHC-selected. Even with non-crossreactive peptides, similar MHC binding motifs lead to the same V alpha 4 gene family dominance, suggesting topography is key.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- T-cell receptor (TCR) variable (V) gene family dominance is observed in T-cell responses to peptide antigens.
- TCR V region interactions with MHC-peptide complexes suggest TCR V-J junctional regions contact peptide epitopes, while other V regions interact with MHC determinants.
- This implies MHC selection can drive V alpha or V beta dominance, potentially even for non-crossreactive peptides if they bind MHC similarly.
Purpose of the Study:
- To investigate if similar MHC binding motifs, induced by minimally substituted peptides, can select for identical V alpha or V beta gene dominance.
- To explore the role of MHC-peptide complex topography in dictating TCR V gene usage.
Main Methods:
- Minimal conservative substitutions were introduced into a synthetic peptide (YYEELLKYYEELLK) presented with an uncommon A beta E alpha d mixed Ia isotype.
- The peptide variant (FFEELLKFFEELLK) was tested for cross-reactivity with the original peptide in T-cell activation assays.
- Dominant TCR V alpha or V beta gene expression was screened in T cells specific for each peptide.
Main Results:
- The variant peptide FFEELLKFFEELLK was non-crossreactive with YYEELLKYYEELLK but retained the same MHC binding motif, restricting T-cell responses to the A beta E alpha isotype.
- Despite non-crossreactivity, T cells specific for both peptides showed dominant expression of the same V alpha 4 gene family members.
- This indicates that the topographical presentation of the peptides by the MHC molecule is a critical factor.
Conclusions:
- The similar topography of the two MHC-peptide complexes functionally selects for a unique A beta E alpha determinant.
- This determinant specifically drives the dominance of the V alpha 4 gene family, irrespective of peptide cross-reactivity.
- MHC-peptide complex topography plays a significant role in shaping the T-cell receptor repertoire selection process.