Characterization of the CD154-positive and CD40-positive cellular subsets required for pathogenesis in retrovirus-induced murine immunodeficiency

Genetically susceptible C57BL/6 (B6) mice that are infected with the LP-BM5 isolate of murine retroviruses develop profound splenomegaly, lymphadenopa thy, hypergammaglobulinemia, terminal B-cell lymphomas, and an immunodefici ency state bearing many similarities to the pathologies seen in AIDS. Becau se of these similarities, this syndrome has been called murine AIDS (MAIDS) . We have previously shown that CD154 (CD40 ligand)-CD40 molecular interact ions are required both for the initiation and progression of MAIDS. Thus, i n vivo anti-CD154 monoclonal antibody (MAb) treatment inhibited MAIDS sympt oms in LP-BM5-infected wild-type mice when either a short course of anti-CD 154 MAb treatment was started on the day of infection or a course was initi ated 3 to 4 weeks after LP-BM5 administration, after disease was establishe d. Here, we further characterize this required CD154-CD40 interaction by a series of adoptive transfer experiments designed to elucidate which cellula r subsets must express CD154 or CD40 for LP-BM5 to induce MAIDS. Specifical ly with regard to CD154 expression, MAIDS-insusceptible B6 nude mice recons tituted with highly purified CD4(+) T cells from wild-type, but not from CD 154 knockout, B6 donors displayed clear MAIDS after LP-BM5 infection. In co ntrast, nude B6 recipients that received CD8(+) T cells from wild-type B6 d onors did not develop MAIDS after LP-BM5 infection. B6 CD40 knockout mice, which are also relatively resistant to LP-BM5-induced MAIDS, became suscept ible to LP-BM5-induced disease after reconstitution with highly purified wi ld-type B cells but not after receiving purified wild-type dendritic cells (DC) or a combined CD40(+) population composed of DC and macrophages obtain ed from B6 SCID mouse donors. Based on these and other experiments, we thus conclude that the cellular basis for the requirement for CD154-CD40 intera ctions for MAIDS induction and progression can be accounted for by CD154 ex pression on CD4(+) T cells and CD40 expression on B cells.