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 2

Reduced LCMV-specific CTL activity and increased viral burden in the absence of 2B4 in vivo.

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Reduced LCMV-specific CTL activity and increased viral burden in the abs...
Splenocytes from uninfected WT donor mice were loaded with LCMV peptides (GP33-41 or NP396-404) or no peptide, labeled with various concentrations (2.5, 1, or 0.4 μM) of CFSE, mixed at equal ratios, and injected (2 × 106 total targets) i.v. into LCMV clone 13–infected recipients (day 4 p.i.) or uninfected WT or 2B4-KO control mice. After 20 hours, spleens were harvested from WT and 2B4-KO recipient mice and analyzed for recovery of each CFSE-labeled target population. (A) Representative histograms demonstrate recovery of NP396-404–labeled (low CFSE), GP33-41–labeled (middle CFSE), and unlabeled (high CFSE) peaks. Numbers represent the percent specific lysis of LCMV peptide–coated targets relative to unlabeled control targets within each experimental mouse. Specific lysis of LCMV peptide–coated targets within individual mice is plotted on the right. Each circle represents an individual mouse, and horizontal lines denote the mean. (B) At various time points after infection, organs were harvested from LCMV clone 13–infected mice, and infectious virus was quantified by standard plaque assay. Titers are plotted as the arithmetic mean ± SD of the log10 of PFU per organ (n = 3–10 mice/group). The y axis lower limit is set at the limit of detection for the liver (log10 2.0) and spleen (log10 1.0) assays. *P < 0.05, **P < 0.01 (2-tailed unpaired Student’s t test). Data are from 1 of 3 experiments with similar results.