Type 1 IFN maintains the survival of anergic CD4+ T cells.
Anergic T cells have immunoregulatory activity and can survive for extended periods in vivo. It is unclear how anergic T cells escape from deletion, because both anergy and apoptosis can occur after TCR ligation. Stimulation of human CD4+ T cell clones reactive to influenza hemagglutinin peptides can occur in the absence of APCs when MHC class II-expressing, activated T cells present peptide to each other. This T:T peptide presentation can induce CD95-mediated apoptosis, while the cells that do not die are anergic. We found that the death after peptide or anti-CD3 treatment of a panel of CD4+ T cell clones is blocked by IFN-beta secreted by fibroblasts and also by IFN-alpha. This increases cell recovery after stimulation, which is not due to T cell proliferation. This mechanism for apoptosis inhibition rapidly stops protein kinase C-delta translocation from the cytoplasm to the nucleus, which is an early event in the death process. A central observation was that CD4+ T cells that are rescued from apoptosis after T:T presentation of peptide by IFN-alphabeta remain profoundly anergic to rechallenge with Ag-pulsed APCs. However, anergized cells retain the ability to respond to IL-2, showing that they are nonresponsive but functional. The prevention of peptide-induced apoptosis in activated T cells by IFN-alphabeta is a novel mechanism that may enable the survival and maintenance of anergic T cell populations after TCR engagement. This has important implications for the persistence of anergic T cells with the potential for immunoregulatory function in vivo.
Lombardi
G
G
Department of Clinical Immunology, Royal Free and University College Medical School, London, United Kingdom.
Dunne
P J
PJ
Scheel-Toellner
D
D
Sanyal
T
T
Pilling
D
D
Taams
L S
LS
Life
P
P
Lord
J M
JM
Salmon
M
M
Akbar
A N
AN
D000938:Antigen-Presenting Cells / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology*; D002470:Cell Survival / Q000276:immunology*; D017635:Clonal Anergy / Q000276:immunology*; D002999:Clone Cells; D018920:Coculture Techniques; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology; D005347:Fibroblasts / Q000737:chemistry / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007370:Interferon Type I / Q000502:physiology*; D016898:Interferon-alpha / Q000502:physiology; D016899:Interferon-beta / Q000502:physiology; D007376:Interleukin-2 / Q000502:physiology; D010455:Peptides / Q000276:immunology / Q000494:pharmacology; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000276:immunology*
D017077:Culture Media, Conditioned; D007370:Interferon Type I; D016898:Interferon-alpha; D007376:Interleukin-2; D010455:Peptides; D016899:Interferon-beta