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Two MHC surface amino acid differences distinguish foreign peptide recognition from autoantigen specificity
1Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Journal of Immunology (Baltimore, Md. : 1950)
|March 10, 2001
Summary
Two specific mutations in MHC molecules, alpha65 and beta78, explain how T cell receptors (TCRs) distinguish between foreign and self-antigens, preventing autoimmune disease like arthritis.
Area of Science:
- Immunology
- Molecular Biology
- Structural Biology
Background:
- KRN T cells recognize foreign peptides on I-A(k) MHC molecules but can cause autoimmune arthritis when interacting with self-antigens on I-A(g7) MHC molecules.
- Five surface amino acid differences between I-A(k) and I-A(g7) influence KRN T cell receptor (TCR) peptide recognition.
Purpose of the Study:
- To investigate the specific roles of two key mutations (alpha65 and beta78) in I-A(k) that mimic I-A(g7) and alter KRN TCR specificity.
- To elucidate the precise molecular mechanisms by which these mutations modulate peptide binding and TCR interaction.
Main Methods:
- Site-directed mutagenesis of I-A(k) to introduce I-A(g7) residues at positions alpha65 and beta78.
- Analysis of KRN TCR recognition of altered I-A(k) molecules presenting foreign (RN peptide) and self (GPI peptide) antigens.
Main Results:
- Mutating I-A(k) at alpha65 and beta78 to their I-A(g7) counterparts enabled KRN TCR recognition of the self-antigen GPI(282--294).
- The alpha65 mutation broadened peptide recognition at P8, while the beta78 mutation alone blocked TCR interaction but, with alpha65, shifted specificity by altering P3 recognition and blocking P8 recognition of the foreign RN peptide.
Conclusions:
- Two specific residues, alpha65 and beta78, in MHC molecules are critical determinants of KRN TCR specificity, differentiating foreign antigen response from autoimmune reactivity.
- Subtle structural changes at the amino acid level within MHC molecules can dictate the balance between effective immunity and the initiation of autoimmune diseases.