Activation-induced CD154 expression abrogates tolerance induced by apoptotic cells.
The decision to generate a productive immune response or tolerance often depends on the context in which T cells first see Ag. Using a classical system of tolerance induction, we examined the immunological consequence of Ag encountered in the presence of naive or activated apoptotic cells. Naive apoptotic cells induced tolerance when injected i.v.; however, previously activated apoptotic cells induced immunity. Further analysis revealed a key role for CD154, as tolerance resulted after i.v. injection of either naive or activated apoptotic CD154(-/-) T cells, while coinjection of an agonistic anti-CD40 mAb with naive apoptotic T cells induced robust immunity. Dendritic cells fed activated apoptotic T cells in vitro produced IL-12p40 in a CD154-dependent manner, and the use of IL-12p40(-/-) mice or mAb-mediated neutralization of IL-12 revealed a link between CD154, IL-12, and the ability of activated apoptotic T cells to induce immunity rather than tolerance. Collectively, these results show that CD154 expression on apoptotic T cells can determine the outcome of an immune response to Ag recognized within the context of the apoptotic cells and suggest that the balance between naive and activated apoptotic T cells may dictate whether a productive immune response is encouraged.
Department of Urology, University of Iowa, Iowa City, IA 52242-1089, USA.
Prajwal
P
Gurung
Tamara A
TA
Kucaba
Thomas A
TA
Ferguson
Thomas S
TS
Griffith
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology*; D007110:Immunity, Active / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D018664:Interleukin-12 / Q000276:immunology / Q000378:metabolism; D053762:Interleukin-12 Subunit p40 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology
D000911:Antibodies, Monoclonal; D019013:CD40 Antigens; D053762:Interleukin-12 Subunit p40; C111390:OVA 323-339; D010446:Peptide Fragments; D023201:CD40 Ligand; D018664:Interleukin-12; D007371:Interferon-gamma; D010047:Ovalbumin