CD100 enhances dendritic cell and CD4+ cell activation leading to pathogenetic humoral responses and immune complex glomerulonephritis.
CD100, a member of the semaphorin family, is a costimulatory molecule in adaptive immune responses by switching off CD72's negative signals. However, CD100's potential pathogenetic effects in damaging immune responses remain largely unexplored. We tested the hypothesis that CD100 plays a pathogenetic role in experimental immune complex glomerulonephritis. Daily injection of horse apoferritin for 14 days induced immune complex formation, mesangial proliferative glomerulonephritis and proteinuria in CD100-intact (CD100+/+) BALB/c mice. CD100-deficient (CD100-/-) mice were protected from histological and functional glomerular injury. They exhibited reduced deposition of Igs and C3 in glomeruli, reduced MCP-1 and MIP-2 intrarenal mRNA expression, and diminished glomerular macrophage accumulation. Attenuated glomerular injury was associated with decreased Ag-specific Ig production, reduced CD4+ cell activation and cytokine production. Following Ag injection, CD4+ cell CD100 expression was enhanced and dendritic cell CD86 expression was up-regulated. However, in CD100-/- mice, dendritic cell CD86 (but not CD80) up-regulation was significantly attenuated. Following i.p. immunization, CD86, but not CD80, promotes early Ag-specific TCR-transgenic DO11.10 CD4+ cell proliferation and IFN-gamma production, suggesting that CD100 expression enables full expression of CD86 and consequent CD4+ cell activation. Transfer of CD100+/+ DO11.10 cells into CD100-/- mice resulted in decreased proliferation demonstrating that CD100 from other sources in addition to CD100 from Ag-specific CD4+ cells plays a role in initial T cell proliferation. Although T cell-B cell interactions also may be relevant, these studies demonstrate that CD100 enhances pathogenetic humoral immune responses and promotes the activation of APCs by up-regulating CD86 expression.
Li
Ming
M
Centre for Inflammatory Diseases, Monash University Department of Medicine, Clayton, Victoria, Australia.
O'Sullivan
Kim M
KM
Jones
Lynelle K
LK
Semple
Timothy
T
Kumanogoh
Atsushi
A
Kikutani
Hitoshi
H
Holdsworth
Stephen R
SR
Kitching
A Richard
AR
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000378:metabolism; D051940:B7-2 Antigen / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D005921:Glomerulonephritis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D007114:Immunization; D007136:Immunoglobulins / Q000276:immunology; D007274:Injections, Intraperitoneal; D007668:Kidney / Q000276:immunology / Q000293:injuries; D008213:Lymphocyte Activation / Q000276:immunology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D039961:Semaphorins / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*
D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; D051940:B7-2 Antigen; C093224:CD100 antigen; D016207:Cytokines; D007136:Immunoglobulins; D039961:Semaphorins