Inducible nitric oxide synthase in T cells regulates T cell death and immune memory.
The progeny of T lymphocytes responding to immunization mostly die rapidly, leaving a few long-lived survivors functioning as immune memory. Thus, control of this choice of death versus survival is critical for immune memory. There are indications that reactive radicals may be involved in this death pathway. We now show that, in mice lacking inducible nitric oxide synthase (iNOS), higher frequencies of both CD4 and CD8 memory T cells persist in response to immunization, even when iNOS(+/+) APCs are used for immunization. Postactivation T cell death by neglect is reduced in iNOS(-/-) T cells, and levels of the antiapoptotic proteins Bcl-2 and Bcl-xL are increased. Inhibitors of the iNOS-peroxynitrite pathway also enhance memory responses and block postactivation death by neglect in both mouse and human T cells. However, early primary immune responses are not enhanced, which suggests that altered survival, rather than enhanced activation, is responsible for the persistent immunity observed. Thus, in primary immune responses, iNOS in activated T cells autocrinely controls their susceptibility to death by neglect to determine the level of persisting CD4 and CD8 T cell memory, and modulation of this pathway can enhance the persistence of immune memory in response to vaccination.
Vig
Monika
M
National Institute of Immunology, New Delhi, India.
Srivastava
Smita
S
Kandpal
Usha
U
Sade
Hadassah
H
Lewis
Virginia
V
Sarin
Apurva
A
George
Anna
A
Bal
Vineeta
V
Durdik
Jeannine M
JM
Rath
Satyajit
S
D000590:Amino Acid Chloromethyl Ketones / Q000378:metabolism; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000201:enzymology* / Q000276:immunology; D016923:Cell Death / Q000502:physiology*; D006801:Humans; D007156:Immunologic Memory / Q000502:physiology*; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D030421:Peroxynitrous Acid / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D016176:T-Lymphocyte Subsets; D051020:bcl-X Protein
D000590:Amino Acid Chloromethyl Ketones; D015703:Antigens, CD; C494811:BCL2L1 protein, human; C494812:Bcl2l1 protein, mouse; D007376:Interleukin-2; D019253:Proto-Oncogene Proteins c-bcl-2; D051020:bcl-X Protein; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D030421:Peroxynitrous Acid; D007371:Interferon-gamma; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse