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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

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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 7

NK cells mediate early loss of highly activated CD8+ T cells in 2B4-KO mice in a perforin-dependent manner.

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NK cells mediate early loss of highly activated CD8+ T cells in 2B4-KO m...
(A) At day 4 of LCMV clone 13 infection, splenocytes (n = 4/group) were gated on Thy 1.2-expressing cells, and the proportion of CD8α+ T cells expressing CD11c was determined. The Thy1.2+CD8α+CD11c+ events were uniformly CD8β+, CD3ε-expressing, and CD44hi. Right: Proportion of CD44hiCD43(1B11)+ events among gated CD8αβ+ T cells. Numbers represent mean (±SD) proportion of gated events. Total numbers (mean ± SEM) of Thy1.2+CD11c+CD8α+ cells were determined in the spleens (B) as well as iLNs (C) of isotype-treated or anti-NK1.1–treated WT and 2B4-KO mice (n = 5/group), as well as in the spleens (D) of similarly treated Prf1-KO and 2B4/Prf1-KO (n = 3–4/group) mice. **P < 0.01 (2-tailed unpaired Student’s t test). Data are from 1 of 3 experiments with similar results.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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