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, Ruth T. Taniguchi, Porunelloor A. Mathew, Vinay Kumar, Raymond M. Welsh
Stephen N. Waggoner, Ruth T. Taniguchi, Porunelloor A. Mathew, Vinay Kumar, Raymond M. Welsh
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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 6

Depletion of NK cells restores LCMV-specific CD8+ T cell responses and viral clearance in 2B4-KO mice to WT levels.

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Depletion of NK cells restores LCMV-specific CD8+ T cell responses and v...
(A–D) One day prior to infection, WT and 2B4-KO mice (n = 4–8/group) were treated with 25 μg isotype (IgG2a) or anti-NK1.1 mAb i.p. (A) Splenic leukocytes (mean ± SD) were enumerated on day 9 p.i. in WT and 2B4-KO mice. (B) Mean proportion (±SD) of IFN-γ+ CD8+ T cells in spleen after GP33-41 stimulation. (C) Viral titers at day 90 p.i. (n = 7–8/group) are displayed as log10 PFU/liver. The horizontal line represents the limit of detection for the plaque assay (log10 2.0). (D) Mean (±SD) fraction of DP thymocytes within thymus of uninfected or day 9 p.i. WT and 2B4-KO mice. (E) A single injection of anti-NK1.1 mAb was administered at various time points (day 0 to day 4) relative to the time of infection with LCMV clone 13. Representative spleen size (photo) and CD44 expression (y axis represents percent of maximum) on splenic CD8+ T cells was determined at day 10 of infection (n = 2 mice/group, mean ± SD). *P < 0.05, **P < 0.01 (2-tailed unpaired Student’s t test). Data are from 1 of 3 experiments with similar results.