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CD4⁺ T Cells from (New Zealand Black x New Zealand White)F₁ Lupus Mice and Normal Mice Immunized Against Apoptotic Nucleosomes Recognize Similar Th Cell Epitopes in the C Terminus of Histone H3¹

Sylvie Fournel^*, Sarah Neichel^*, Hayet Dali^*, Sandrine Farci, Bernard Maillère, Jean-Paul Briand^* and Sylviane Muller^2,*

^* Institut de Biologie Moléculaire et Cellulaire, Unité Propre de Recherche 9021, Centre National de la Recherche Scientifique, and Université Louis Pasteur, Strasbourg, France; and CEA Saclay, Département d’Ingénierie et d’Etudes des Protéines, Gif-sur-Yvette, France

We have previously reported that peptide 88-99 of histone H4 represents a minimal T cell epitope recognized by Th cells from nonautoimmune BALB/c (H-2^d/d) mice immunized with nucleosomes. In this study, we tested a panel of overlapping peptides spanning the whole sequences of H4 and H3 for recognition by CD4⁺ T cells from unprimed (New Zealand Black (NZB) x New Zealand White (NZW))F₁ lupus mice (H-2^d/z). None of the 11 H4 peptides was recognized by CD4⁺ T cells from (NZB x NZW)F₁ mice. In contrast, these cells proliferated and secreted IL-2, IL-10, and IFN- upon ex vivo stimulation with H3 peptides representing sequences 53-70, 64-78, and 68-85. Peptides 56-73 and 61-78 induced the production of IFN- and IL-10, respectively, without detectable proliferation, suggesting that they may act as partial agonist of the TCR. Th cells from unprimed BALB/c mice and other lupus-prone mice such as SNF₁ (H-2^d/q) and MRL/lpr (H-2^k/k) mice did not recognize any peptides present within the H3 region 53-85. We further demonstrated that immunization of normal BALB/c mice with syngeneic liver nucleosomes and spleen apoptotic cells, but not with nonapoptotic syngeneic cells, induced Th cell responses against several peptides of the H3 region 53-85. Moreover, we found that this conserved region of H3, which is accessible at the surface of nucleosomes, is targeted by Abs from (NZB x NZW)F₁ mice and lupus patients, and contains motifs recognized by several distinct HLA-DR molecules. It might thus be important in the self-tolerance breakdown in lupus.

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				S Muller, J Dieker, A Tincani, and P. Meroni Pathogenic anti-nucleosome antibodies Lupus, May 1, 2008; 17(5): 431 - 436. [Abstract] [PDF]

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