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T cells discriminate between differentially phosphorylated forms of αB-crystallin, a major central nervous system myelin antigen

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Author: Stipdonk, M.J.B. van · Willems, A.A. · Amor, S. · Persoon-Deen, C. · Travers, P.J. · Boog, C.J.P. · Noort, J.M. van
Institution: TNO Preventie en Gezondheid
Source:International Immunology, 7, 10, 943-950
Identifier: 234546
doi: doi:10.1093/intimm/10.7.943
Keywords: Health · αB-crystallin · Epitope analysis · Heal shock protein · I-A(s) binding motif · Phosphorylation · Post-translational modification · TCR · Amino Acid Sequence · Animals · Binding Sites · Cattle · Computer Simulation · Crystallins · Epitopes · Female · Lymphocyte Activation · Mice · Mice, Inbred Strains · Models, Molecular · Molecular Sequence Data · Phosphorylation · Receptors, Antigen, T-Cell · Serine · T-Lymphocytes


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-2(S)) mice to αB-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-A(S). 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 αB-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-A(S) 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 αB-crystallin creates neo-determinants for T cells and, therefore, may contribute to the breakdown of peripheral tolerance to this self protein.