Superantigen-induced CD4 T cell tolerance mediated by myeloid cells and IFN-gamma.
We have previously shown that systemic staphylococcal enterotoxin A (SEA) injections cause CD4 T cells in TCR-transgenic mice to become tolerant to subsequent ex vivo restimulation. An active IFN-gamma-dependent mechanism of suppression was responsible for the apparent unresponsiveness of the CD4 T cells. In this study, we analyze the response of CD4 T cells isolated throughout the first 10 days of the in vivo response to injected SEA. We show that CD4 T cells isolated at the peak of the in vivo response undergo very little activation-induced cell death after sterile FACS sorting or restimulation in the presence of neutralizing Abs to IFN-gamma. We also show that the IFN-gamma-dependent tolerance develops soon after SEA injection in the spleens of both normal and TCR-transgenic mice. This suppression is dependent upon myeloid cells from the SEA-treated mice and is optimal when inducible NO synthase activity and reactive oxygen intermediates are both present. The data indicate that IFN-gamma, myeloid cells, and a combination of NO and reactive oxygen intermediates all contribute to a common pathway of T cell death that targets activated or responding CD4 T cells. Sorted Gr-1(+) cells from SEA-treated mice also directly suppress the response of naive CD4 T cells in mixed cultures, indicating that this tolerance mechanism may play a role in down-regulating other vigorous immune responses.
Cauley
L S
LS
Trudeau Institute, Saranac Lake, NY 12983, USA.
Miller
E E
EE
Yen
M
M
Swain
S L
SL
D000818:Animals; D015214:Antigens, Differentiation, Myelomonocytic / Q000096:biosynthesis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002460:Cell Line; D002469:Cell Separation; D002478:Cells, Cultured; D004768:Enterotoxins / Q000008:administration & dosage / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D007275:Injections, Intravenous; D007371:Interferon-gamma / Q000502:physiology*; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D022423:Myeloid Cells / Q000276:immunology* / Q000378:metabolism; D009569:Nitric Oxide / Q000502:physiology; D017382:Reactive Oxygen Species / Q000276:immunology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis; D013154:Spleen / Q000276:immunology; D013211:Staphylococcus aureus / Q000276:immunology; D018089:Superantigens / Q000008:administration & dosage / Q000276:immunology*; D018800:Thy-1 Antigens / Q000096:biosynthesis
D015214:Antigens, Differentiation, Myelomonocytic; D004768:Enterotoxins; D017382:Reactive Oxygen Species; D016693:Receptors, Antigen, T-Cell, alpha-beta; D018089:Superantigens; D018800:Thy-1 Antigens; D009569:Nitric Oxide; C026066:enterotoxin A, Staphylococcal; D007371:Interferon-gamma