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Secondary anchor polymorphism in the HA-1 minor histocompatibility antigen critically affects MHC stability and TCR recognition.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2009 Mar 10; Vol. 106 (10), pp. 3889-94. Date of Electronic Publication: 2009 Feb 20. - Publication Year :
- 2009
-
Abstract
- T cell recognition of minor histocompatibility antigens (mHags) underlies allogeneic immune responses that mediate graft-versus-host disease and the graft-versus-leukemia effect following stem cell transplantation. Many mHags derive from single amino acid polymorphisms in MHC-restricted epitopes, but our understanding of the molecular mechanisms governing mHag immunogenicity and recognition is incomplete. Here we examined antigenic presentation and T-cell recognition of HA-1, a prototypic autosomal mHag derived from single nucleotide dimorphism (HA-1(H) versus HA-1(R)) in the HMHA1 gene. The HA-1(H) peptide is restricted by HLA-A2 and is immunogenic in HA-1(R/R) into HA-1(H) transplants, while HA-1(R) has been suggested to be a "null allele" in terms of T cell reactivity. We found that proteasomal cleavage and TAP transport of the 2 peptides is similar and that both variants can bind to MHC. However, the His>Arg change substantially decreases the stability and affinity of HLA-A2 association, consistent with the reduced immunogenicity of the HA-1(R) variant. To understand these findings, we determined the structure of an HLA-A2-HA-1(H) complex to 1.3A resolution. Whereas His-3 is accommodated comfortably in the D pocket, incorporation of the lengthy Arg-3 is predicted to require local conformational changes. Moreover, a soluble TCR generated from HA-1(H)-specific T-cells bound HA-1(H) peptide with moderate affinity but failed to bind HA-1(R), indicating complete discrimination of HA-1 variants at the level of TCR/MHC interaction. Our results define the molecular mechanisms governing immunogenicity of HA-1, and highlight how single amino acid polymorphisms in mHags can critically affect both MHC association and TCR recognition.
- Subjects :
- ATP Binding Cassette Transporter, Subfamily B, Member 2
ATP-Binding Cassette Transporters metabolism
Arginine metabolism
Cell Separation
Circular Dichroism
Crystallography, X-Ray
Epitopes chemistry
Epitopes immunology
HLA-A2 Antigen chemistry
Humans
Leukemia, Myelogenous, Chronic, BCR-ABL Positive immunology
Proteasome Endopeptidase Complex metabolism
Protein Binding
Protein Stability
Protein Structure, Secondary
Protein Transport
Receptors, Antigen, T-Cell chemistry
Surface Plasmon Resonance
T-Lymphocytes, Cytotoxic immunology
Tissue Donors
Minor Histocompatibility Antigens chemistry
Minor Histocompatibility Antigens genetics
Polymorphism, Genetic
Receptors, Antigen, T-Cell immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 106
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 19234124
- Full Text :
- https://doi.org/10.1073/pnas.0900411106