Identification of a minimal T cell epitope recognized by antinucleosome Thcells in the C-terminal region of histone H4

Autoreactive T cells responding to systemic autoantigens have been characte rized in patients and mice with autoimmune diseases and in healthy individu als. Using peptides covering the whole sequence of histone H4, we character ized several epitopes recognized by lymph node Th cells from nonsystemic lu pus erythematosus-prone mice immunized with the same peptides, the H4 prote in, or nucleosomes, Multiple T epitopes were identified after immunizing H- 2(d) BALB/c mice with H4 peptides, They spanned residues 28-42, 30-47, 66-8 3, 72-89, and 85-102, Within the region 85-102, a minimal CD4(+) T epitope containing residues 88-99 was characterized. Although Abs to peptide 88-99 recognized H4, this peptide does not contain a dominant B cell epitope reco gnized by anti-H4 Abs raised in BALB/c mice or Abs from NZB/NZW H-2(d/z) lu pus mice. Th cells primed in vivo with H4 responded to H4, but not to pepti de 88-99, However, this peptide was able to stimulate the proliferation and IL-2 secretion of Th cells generated after immunization with nucleosomes. H4(88-99) thus represents a cryptic epitope with regard to H4 and a suprado minant- epitope presented by nucleosome, a supramolecular complex that play s a key role in lupus, This study shows that in the normal repertoire of na ive BALB/c mice, autoreactive Th cells specific for histones are not delete d. The reactivity of these Th cells seems to be relatively restricted and r esembles that of Th clones generated from SNF1 ((SWR x NZB)F-1; I-A(d/q)) l upus mice described earlier.