T cells discriminate between differentially phosphorylated forms of alphaB-crystallin, a major central nervous system myelin antigen.
Factors such as developmental stage or physiological and infectious stress may change patterns of post-translational protein modification. In order to determine whether such regulated types of modification may influence T cell responsiveness to self proteins we examined the T cell response of SJL (H-2s) mice to alphaB-crystallin, a small heat shock protein that can exist in differentially phosphorylated forms. Epitope mapping revealed the presence of two T cell epitopes that are presented by I-As. One major epitope including residues 41-56 contains an amino acid residue (Ser45) that can be phosphorylated as the result of aging or stress. Accordingly, T cells from SJL mice discriminate between preparations of alphaB-crystallin that differ in their extent of phosphorylation at the level of whole protein as well as at the level of determinant-specific responses. Phosphorylation at Ser45 does not prevent binding of the peptide 41-56 to I-As and computer-assisted modelling of the peptide-MHC complex suggests that the phosphate group of the bound peptide extends outwards from the peptide-binding cleft and may thus be available for direct contact with TCR. Together, our data provide evidence that stress-inducible phosphorylation of alphaB-crystallin creates neo-determinants for T cells and, therefore, may contribute to the breakdown of peripheral tolerance to this self protein.
van Stipdonk
M J
MJ
Division of Immunological and Infectious Diseases, TNO Prevention and Health, Leiden, The Netherlands.
Willems
A A
AA
Amor
S
S
Persoon-Deen
C
C
Travers
P J
PJ
Boog
C J
CJ
van Noort
J M
JM
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002417:Cattle; D003198:Computer Simulation; D003459:Crystallins / Q000276:immunology* / Q000378:metabolism*; D000939:Epitopes / Q000276:immunology; D005260:Female; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008815:Mice, Inbred Strains; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010766:Phosphorylation; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D003459:Crystallins; D000939:Epitopes; D011948:Receptors, Antigen, T-Cell; D012694:Serine