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 H3.
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))F(1) lupus mice (H-2(d/z)). None of the 11 H4 peptides was recognized by CD4(+) T cells from (NZB x NZW)F(1) mice. In contrast, these cells proliferated and secreted IL-2, IL-10, and IFN-gamma 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-gamma 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 SNF(1) (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)F(1) 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.
Fournel
Sylvie
S
Institut de Biologie Moléculaire et Cellulaire, Unité Propre de Recherche 9021, Centre National de la Recherche Scientifique, and Université Louis Pasteur, Strasbourg, France.
Neichel
Sarah
S
Dali
Hayet
H
Farci
Sandrine
S
Maillère
Bernard
B
Briand
Jean-Paul
JP
Muller
Sylviane
S
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation / Q000235:genetics; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002478:Cells, Cultured; D003433:Crosses, Genetic; D018985:Epitopes, B-Lymphocyte / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006183:H-2 Antigens / Q000378:metabolism; D006681:HLA-D Antigens / Q000276:immunology / Q000378:metabolism; D064532:Histocompatibility Antigen H-2D; D006657:Histones / Q000276:immunology* / Q000378:metabolism; D006720:Homozygote; D007114:Immunization; D007074:Immunoglobulin G / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000276:immunology; D008181:Lupus Nephritis / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D008814:Mice, Inbred NZB; D008969:Molecular Sequence Data; D009707:Nucleosomes / Q000276:immunology* / Q000637:transplantation; D010446:Peptide Fragments / Q000276:immunology* / Q000378:metabolism; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D014185:Transplantation, Isogeneic
D018985:Epitopes, B-Lymphocyte; D018984:Epitopes, T-Lymphocyte; D006183:H-2 Antigens; D006681:HLA-D Antigens; D064532:Histocompatibility Antigen H-2D; D006657:Histones; D007074:Immunoglobulin G; D009707:Nucleosomes; D010446:Peptide Fragments