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Journal of Virology, March 2008, p. 2456-2469, Vol. 82, No. 5
0022-538X/08/$08.00+0     doi:10.1128/JVI.01665-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

The Programmed Death-1 and Interleukin-10 Pathways Play a Down-Modulatory Role in LP-BM5 Retrovirus-Induced Murine Immunodeficiency Syndrome{triangledown}

Kathy A. Green,1 Taku Okazaki,2 Tasuku Honjo,2 W. James Cook,1,{dagger} and William R. Green1*

Department of Microbiology and Immunology, Dartmouth Medical School, and Norris Cotton Cancer Center, Lebanon, New Hampshire 03756,1 Department of Immunology and Genomic Medicine, Graduate School of Medicine, Kyoto University, Yoshida-Konoe, Sakyo-ku, Kyoto 606-8501, Japan2

Received 31 July 2007/ Accepted 11 December 2007

Pathology due to the immune system's response to viral infections often represents a delicate balance between inhibition of viral pathogenesis and regulation of protective immunity. In susceptible C57BL/6 (B6) mice, the murine retroviral isolate LP-BM5 induces splenomegaly, hypergammaglobulinemia, profound B- and T-cell immunodeficiency, and increased susceptibility to opportunistic pathogens and terminal B-cell lymphomas. Here, we report that B6.PD-1 (programmed death-1) and B6.IL-10 knockout mice are substantially more susceptible to LP-BM5-induced disease than wild-type B6 mice. LP-BM5-infected B6.PD-1–/– mice developed more severe splenomegaly, hypergammaglobulinemia, and immunodeficiency than infected B6 mice: PD-1–/– mice are more susceptible to lower doses of LP-BM5 and show more exaggerated disease early postinfection. LP-BM5-infected B6.IL-10–/– mice also develop exaggerated LP-BM5-induced disease, compared to B6 mice, without a significant change in the retroviral load. By reciprocal reconstitution experiments, comparing wild-type versus PD-1–/– sources of the requisite cells for LP-BM5 pathogenesis—CD4 T and B cells, PD-1+ B cells appear to be crucial in the normal limitation of LP-BM5-induced disease in B6 mice. Also, infected B6 mice have increased CD11b+ spleen cells that express interleukin-10 (IL-10). However, PD-1–/– mice, though showing an even greater expansion of CD11b+ cells after LP-BM5 inoculation, did not show an equivalent increase in IL-10-producing cells. Thus, it appears that PD-1/PD-L interactions and IL-10 are primarily important in moderating the effects of LP-BM5-induced disease in B6 mice.

* Corresponding author. Mailing address: Department of Microbiology and Immunology, Dartmouth Medical School, 1 Medical Center Drive, Lebanon, NH 03756. Phone: (603) 650-5056. Fax: (603) 650-6223. E-mail: kathy.a.green{at}dartmouth.edu

{triangledown} Published ahead of print on 19 December 2007.

{dagger} Present address: GlycoFi/Merck & Co., Inc., Lebanon, NH 03766.

Journal of Virology, March 2008, p. 2456-2469, Vol. 82, No. 5
0022-538X/08/$08.00+0     doi:10.1128/JVI.01665-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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