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 stressmay change patterns of post-translational protein modification. In order todetermine whether such regulated types of modification may influence T cellresponsiveness to self proteins we examined the T cell response of SJL(H-2s) mice to alphaB-crystallin, a small heat shock protein that can existin differentially phosphorylated forms. Epitope mapping revealed thepresence of two T cell epitopes that are presented by I-As. One majorepitope including residues 41-56 contains an amino acid residue (Ser45)that can be phosphorylated as the result of aging or stress. Accordingly, Tcells from SJL mice discriminate between preparations of alphaB-crystallinthat differ in their extent of phosphorylation at the level of wholeprotein as well as at the level of determinant-specific responses.Phosphorylation at Ser45 does not prevent binding of the peptide 41-56 toI-As and computer-assisted modelling of the peptide-MHC complex suggeststhat the phosphate group of the bound peptide extends outwards from thepeptide-binding cleft and may thus be available for direct contact withTCR. Together, our data provide evidence that stress-induciblephosphorylation of alphaB- crystallin creates neo-determinants for T cellsand, therefore, may contribute to the breakdown of peripheral tolerance tothis self protein.