The H4b minor histocompatibility antigen is caused by a combination of genetically determined and posttranslational modifications.
Minor histocompatibility (H) Ag disparities result in graft-vs-host disease and chronic solid allograft rejection in MHC-identical donor-recipient combinations. Minor H Ags are self protein-derived peptides presented by MHC class I molecules. Most arise as a consequence of allelic variation in the bound peptide (p) that results in TCR recognizing the p/MHC as foreign. We used a combinational peptide screening approach to identify the immune dominant H2K(b)-restricted epitope defining the mouse H4(b) minor H Ag. H4(b) is a consequence of a P3 threonine to isoleucine change in the MHC-bound peptide derived from epithelial membrane protein-3. This allelic variation also leads to phosphorylation of the H4(b) but not the H4(a) epitope. Further, ex vivo CD8(+) T lymphocytes bind phosphorylated Ag tetramers with high efficiency. Although we document the above process in the minor H Ag system, posttranslational modifications made possible by subtle amino acid changes could also contribute to immunogenicity and immune dominance in tumor immunotherapeutic settings.
Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Rajwardhan
R
Yadav
Yoshitaka
Y
Yoshimura
Alina
A
Boesteanu
Gregory J
GJ
Christianson
Wilfred U
WU
Ajayi
R
R
Shashidharamurthy
Aleksandar K
AK
Stanic
Derry C
DC
Roopenian
Sebastian
S
Joyce
D019943:Amino Acid Substitution / Q000276:immunology; D000818:Animals; D020650:Combinatorial Chemistry Techniques; D017124:Conserved Sequence / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000235:genetics / Q000378:metabolism; D006183:H-2 Antigens / Q000235:genetics* / Q000378:metabolism*; D006801:Humans; D016056:Immunodominant Epitopes / Q000235:genetics / Q000378:metabolism; D007532:Isoleucine / Q000378:metabolism; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens / Q000235:genetics / Q000378:metabolism; D008912:Minor Histocompatibility Loci / Q000235:genetics*; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism; D019151:Peptide Library; D010748:Phosphopeptides / Q000235:genetics / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000235:genetics* / Q000276:immunology*; D013912:Threonine / Q000378:metabolism
C485157:EMP3 protein, human; C113389:Emp3 protein, mouse; C485158:Emp3 protein, rat; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; C032876:H-2Kb protein, mouse; D016056:Immunodominant Epitopes; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D015778:Minor Histocompatibility Antigens; D009842:Oligopeptides; D019151:Peptide Library; D010748:Phosphopeptides; C114735:minor H antigen H60; D007532:Isoleucine; D013912:Threonine