The programmed death-1 and interleukin-10 pathways play a down-modulatory role in LP-BM5 retrovirus-induced murine immunodeficiency syndrome.
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.
Green
Kathy A
KA
Department of Microbiology and Immunology, Dartmouth Medical School, 1 Medical Center Drive, Lebanon, NH 03756, USA. kathy.a.green@dartmouth.edu
Okazaki
Taku
T
Honjo
Tasuku
T
Cook
W James
WJ
Green
William R
WR
D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D007153:Immunologic Deficiency Syndromes / Q000503:physiopathology*; D016753:Interleukin-10 / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D012190:Retroviridae / Q000502:physiology*
D051017:Apoptosis Regulatory Proteins; D016753:Interleukin-10