Inducible nitric oxide synthase in T cells regulates T cell death and immune memory
Monika Vig, … , Jeannine M. Durdik, Satyajit Rath
Monika Vig, … , Jeannine M. Durdik, Satyajit Rath
Published June 15, 2004
Citation Information: J Clin Invest. 2004;113(12):1734-1742. https://doi.org/10.1172/JCI20225.
View: Text | PDF
Article Immunology

Inducible nitric oxide synthase in T cells regulates T cell death and immune memory

Abstract

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.

Authors

Monika Vig, Smita Srivastava, Usha Kandpal, Hadassah Sade, Virginia Lewis, Apurva Sarin, Anna George, Vineeta Bal, Jeannine M. Durdik, Satyajit Rath

×

Figure 2

Options: View larger image (or click on image) Download as PowerPoint
Higher frequencies of cytokine-secreting CD4 and CD8 memory T cells in i...
Higher frequencies of cytokine-secreting CD4 and CD8 memory T cells in iNOS–/– mice. (A_D) T cell memory responses 6 weeks after immunization of WT or iNOS–/– mice with OVA1 and OVA2 peptides (+ peptide) or with adjuvant alone (_ peptide), by restimulation with (+) or without (-) either OVA2 (A) or OVA1 (B) peptide, followed by flow cytometric analysis of the CD4 (A) or CD8 (B) cells for expression of CD44 versus intracellular IFN-γ. The frequencies of IFN-γ_expressing CD4 (C) or CD8 (D) cells in groups of WT or iNOS–/– mice immunized with peptides (gray bars) or with adjuvant alone (white bars) are shown as mean ± SE (n = 3).