The animal immune system provides defence against microbial infection, and the evolution of certain animal–microbial symbioses is predicted to involve adaptive changes in the host immune system to accommodate the microbial partner. For example, the reduced humoral immune system in the pea aphidAcyrthosiphon pisum, including an apparently non-functional immune deficiency (IMD) signalling pathway and absence of peptidoglycan recognition proteins (PGRPs), has been suggested to be an adaptation for the symbiosis with the bacteriumBuchnera aphidicola. To investigate this hypothesis, the interaction betweenBuchneraand non-host cells, specifically culturedDrosophilaS2 cells, was investigated. Microarray analysis of the gene expression pattern in S2 cells indicated thatBuchneratriggered an immune response, including upregulated expression of genes for antimicrobial peptides via the IMD pathway with the PGRP-LC as receptor.Buchneracells were readily taken up by S2 cells, but were subsequently eliminated over 1–2 days. These data suggest thatBuchnerainduces in non-host cells a defensive immune response that is deficient in its host. They support the proposed contribution of theBuchnerasymbiosis to the evolution of the apparently reduced immune function in the aphid host.