The mechanism of nasal tolerance in lupus prone mice is T-cell anergy induced by immature B cells that lack B7 expression.
To determine if B cells of lupus prone NZB mice possess intrinsic defects that directly lead or contribute to T-cell hyper-responsiveness, we injected age-, sex- and MHC II-matched NZB and Balb/c mice with histone peptide H471 representing a dominant Th cell epitope in histone H4 of the nucleosome. We found that B220+ B cells of NZB mice express high levels of surface CD86 following antigen priming. We cocultured CD4+ T and B220+ B cells of naïve or peptide primed NZB and Balb/c mice in the presence of peptide. Antigen presentation by autoimmune B cells of NZB mice induced hyper-responsiveness from normal CD4+ T cells of Balb/c mice. T-cell hyper-responsiveness is a result of CD86 costimulation by B cells of NZB mice. Induction of nasal tolerance to H471 in NZB mice suppressed CD86 surface expression and led to downregulation of T-cell proliferative response and cytokine production. More interestingly, B220+ B cells from nasally tolerized NZB mice induced T-cell anergy to anti-CD3 and anti-CD28 antibody stimulation in vitro. The anergic T cells do not possess suppressive function in coculture with naïve responder T cells nor produce suppressive cytokines interleukin 10 and transforming growth factor-beta in vitro.
Wu
Henry Yim
HY
Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA. hwu@rics.bwh.harvard.edu
Monsonego
Alon
A
Weiner
Howard L
HL
D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D017951:Antigen Presentation / Q000276:immunology; D000938:Antigen-Presenting Cells / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D051940:B7-2 Antigen / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D017635:Clonal Anergy / Q000276:immunology*; D018920:Coculture Techniques; D015536:Down-Regulation; D005260:Female; D006657:Histones / Q000737:chemistry / Q000276:immunology; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000276:immunology; D017493:Leukocyte Common Antigens / Q000032:analysis / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008814:Mice, Inbred NZB; D009666:Nose / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology
D051940:B7-2 Antigen; D006657:Histones; D016056:Immunodominant Epitopes; D017493:Leukocyte Common Antigens