PD-1 plays a downmodulatory role in a murine immunodeficiency syndrome (43.26)

Abstract

Abstract An immunodeficiency syndrome is induced by infection of C57BL/6 (B6) with the murine leukemia virus LP-BM5. Other labs have shown that this syndrome requires CD4 T and B cell interactions. We have found it to be dependent on: CD154/CD40 and CD40 associated TRAF 6 and nondependent on CD80 and CD86. Gene chip analysis on spleen cells from LP-BM5 infected B6 mice revealed that the PD-1 and IL-10 genes are highly expressed after LP-BM5 infection. PD-1, a transmembrane cellular protein, was originally identified in a T cell line undergoing cell death and its ligation is generally considered to result in negative regulation of immune cell interactions and responses. We examined the role of PD-1 in LP-BM5 induced immunodeficiency via the use of B6.PD-1 k.o. mice and found that they develop substantially more severe disease than w.t. mice, as a function of; viral dose delivered in vivo and kinetics. PD-1 ligands, PD-L1, and PD-L2 have been identified, and flow cytometry shows that PD-L1 is preferentially upregulated during in vivo LP-BM5 infection. In in vivo antibody blocking studies, after LP-BM5 infection, anti-PD-L1, but not anti-PD-L2 treatment led to exaggerated disease. Other labs have reported that PD-L1 ligation of PD-1 leads to increased IL-10 production. We have found IL-10 k.o. mice are more susceptible to LP-BM5 induced immunodeficiency than w.t. mice. Thus, PD-1/PD-L1 and IL-10 pathways both appear to play roles in the moderation of LP-BM5 pathogenesis. Adoptive transfer experiments, using combinations of w.t., vs PD-1 k.o., CD4 T vs B cells to reconstitute LP-BM5 infected Rag 1 k.o. mice, suggest that B-cell expressed PD-1 is critical for the moderation of LP-BM5 induced pathogenesis.