Absence of mouse 2B4 promotes NK cell–mediated killing of activated CD8+ T cells, leading to prolonged viral persistence and altered pathogenesis
Stephen N. Waggoner, … , Vinay Kumar, Raymond M. Welsh
Stephen N. Waggoner, … , Vinay Kumar, Raymond M. Welsh
Published May 3, 2010
Citation Information: J Clin Invest. 2010;120(6):1925-1938. https://doi.org/10.1172/JCI41264.
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Research Article Immunology

Absence of mouse 2B4 promotes NK cell–mediated killing of activated CD8+ T cells, leading to prolonged viral persistence and altered pathogenesis

Abstract

Persistent viral infections are often associated with inefficient T cell responses and sustained high-level expression of inhibitory receptors, such as the NK cell receptor 2B4 (also known as CD244), on virus-specific T cells. However, the role of 2B4 in T cell dysfunction is undefined, and it is unknown whether NK cells contribute to regulation of these processes. We show here that persistent lymphocytic choriomeningitis virus (LCMV) infection of mice lacking 2B4 resulted in diminished LCMV-specific CD8+ T cell responses, prolonged viral persistence, and spleen and thymic pathologies that differed from those observed in infected wild-type mice. Surprisingly, these altered phenotypes were not caused by 2B4 deficiency in T cells. Rather, the entire and long-lasting pathology and viral persistence were regulated by 2B4-deficient NK cells acting early in infection. In the absence of 2B4, NK cells lysed activated (defined as CD44hi) but not naive (defined as CD44lo) CD8+ T cells in a perforin-dependent manner in vitro and in vivo. These results illustrate the importance of NK cell self-tolerance to activated CD8+ T cells and demonstrate how an apparent T cell–associated persistent infection can actually be regulated by NK cells.

Authors

Stephen N. Waggoner, Ruth T. Taniguchi, Porunelloor A. Mathew, Vinay Kumar, Raymond M. Welsh

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Figure 1

Reduced magnitude of the LCMV-specific CD8+ T cell response during persistent LCMV clone 13 infection of 2B4-KO mice.

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Reduced magnitude of the LCMV-specific CD8+ T cell response during persi...
(A) Representative viral peptide–induced IFN-γ expression by splenic T cells 9 days after infection with 2 × 106 PFU LCMV clone 13 i.v. Numbers represent mean ± SD of the percentage of IFN-γ+ CD4+ or CD8+ T cells from all the similarly treated mice in the experiment (n = 4). (B) Proportions of LCMV GP33-41–stimulated IFN-γ+ splenic or peripheral blood CD8+ T cells are plotted as mean ± SEM (n = 3–8/group) across a range of time points during persistent LCMV clone 13 infection. (C) Total numbers (mean ± SEM) of GP33-41– and NP396-404–specific IFN-γ+ splenic CD8+ T cells in WT and 2B4-KO mice (n = 10–15/group) at day 6 of infection. (D) Representative CD8+ T cell IFN-γ expression (mean ± SD) in the blood (n = 4) at day 35 of LCMV clone 13 infection. (E) IFN-γ responses (mean ± SD) by GP33-41–specific CD8+ T cells in the iLNs and lungs of WT and 2B4-KO mice (n = 3–4/group) at days 6 and 21 of LCMV clone 13 infection. (F and G) Frequencies (mean ± SEM) of day 6 (n = 6–11/group) LCMV NP396/Db (F) and day 8 (n = 8/group) GP33/Db (G) tetramer-binding CD8+ T cells in the spleen. *P < 0.05, **P < 0.01 (2-tailed unpaired Student’s t test). Data are from 1 of 3–4 experiments with similar results.