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.
Yadav
Rajwardhan
R
Department of Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
Yoshimura
Yoshitaka
Y
Boesteanu
Alina
A
Christianson
Gregory J
GJ
Ajayi
Wilfred U
WU
Shashidharamurthy
R
R
Stanic
Aleksandar K
AK
Roopenian
Derry C
DC
Joyce
Sebastian
S
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