Projects per year
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.
Original language | English |
---|---|
Pages (from-to) | 3889-94 |
Number of pages | 6 |
Journal | National Academy of Sciences. Proceedings |
Volume | 106 |
Issue number | 10 |
DOIs | |
Publication status | Published - 10 Mar 2009 |
Keywords
- stem cell transplantation
- graft-versus-leukemia
- major histocompatibility complex
Fingerprint
Dive into the research topics of 'Secondary anchor polymorphism in the HA-1 minor histocompatibility antigen critically affects MHC stability and TCR recognition'. Together they form a unique fingerprint.Projects
- 2 Finished
-
The Development of Cellular Therapy for the Correction of CMV-Specific Immunodeficiency After Stem Cell Transplantation
Cobbold, M.
1/07/03 → 31/07/09
Project: Research Councils
-
A Biophysical Approach Towards Exploiting the Clinical Potential of Alloreactive T-Cell Recognition
Young, L.
3/03/03 → 28/02/07
Project: Research Councils