Lymphocytes play the music but the macrophage calls the tune Werner Solbach, Heidrun Moll and Martin Röllinghoff Macrophages as hosts for microbes The fate of intracellular parasites is strongly influenced by their mech- anis m of attachment to, and pen- etration of, host cells. Toxoplasma gondii tachyzoites, for example, can either actively invade their host and survive or can be phagocytosed and arekilled (K.Joiner, New Haven). In the former case, laminin adsorbed to the tachyzoite surface binds to the integrin-ßl receptors on the cell surface. Entering via this route, T oxoplasma take up residence in vacuoles that exdude host mem- brane glycoproteins. Such vacuoles fail to fuse with acidifying lysosomes and endosomes thus protecting the parasites from lethaI host responses. However, jf the tachyzoites are coated with antibody, they are bound by macrophage Fc receptors (FcR); the blocks in fusion and acidi- fication of the vacuoles are overcome and the microbes are killed by trig- gering the macrophage's respiratory burst. The mechanism of this FcR- mediated reversal of the block in fusion and acidification is not yet dear but studies using respiratory- burst-negative ceIls transfected with various FcR mutants have shown that distinct domains of the cyto- plasmic tail of the FcR direct endo- cytosis and phagocytosis. Leishmania adopt a different en- try and survival strategy. They pass- ively attach to various receptors, including complement receptors, on the host cell surface by means of lipophosphoglycan and gp63 and are taken up by conventional phagocytosis. Leishmania-conraining phagosomes fuse effectively with lysosomes, as shown by the presence of lysosomal enzymes within the parasitophorous vacuole (D. RusselI; St Louis) and kinetic studies have revealed that a constant supply of lysosomal enzymes is likely to be released into these vacuoles. The Researchers interested in immunologi- caJ aspects of bacterial, fungal, pro- tozoan and helminthic infection are too often kept apart by artificial sub- ject boundaries. These barriers were temporarily breached by arecent workshop * in which the comp/ex in- terplay between microbes and their mammalian hosts were examined (rom aglobai viewpoint. The role of T-cell subsets and their products came under dose scrutiny but the most forceful image was that of the macrophage. As host for infective agents, as modulator of specific immune activity and as ulti- mate mediator of the host response, the macrophage plays a virtuoso's role in the host-parasite drama. magnitude of the respiratory burst is decreased when triggered by complement-coated parasites, so that the mechanism of entry may contribute in more than one way to the survival of the parasite. Macrophages as antigen-presenting cells (APCs) Two major pathways have evolved for the presentation of anti- gen to T cells. Intracellular antigens are mainly processed in the cytosol and are presented in the context of MHC dass I molecules, whereas ex- ogenous antigens are generally pro- cessed by the endosomal pathway and associate with MHC dass 11 molecules. P. Kaye (London), work- ing with Leishmania donovani, showed that phagolysosomes of infected macrophages contain para- sites in various stages of degra- dation. Although MHC dass 11 mol- ecules could be seen within the phagolysosomes, they are not used *The Fourth International Erlangen Workshop on Moleeular Aspects of Im- munological Host-Parasite Interactions was held at Erlangen, FRG on 27-29 September 1990. It was organized by M. Röllinghoff, W. Solbach and J. Kalden. © 1991, Elsevier Scicnce Publishers Ltd, UK. 0167--4919/91/$02.00 Immunology Today 4 Vol. 12, No. 1 1991 for antigen presentation: the meta- bolie inhibitor Brefeldin-A abro- ga ted the presentation of parasite antigens to MHC dass-II-restricted T cells. Brefeldin-A blocks the trans- port of newly synthesized proteins from the endoplasmic reticulum to the Golgi apparatus, suggesting that only nascent MHC molecules are used by APCs. The macrophage as an APC plays a key role in determining whether or not a cellular immune response pro- motes protection of the host or sur- vival of the infectious agent. One important factor is the level of ex- pression of MHC molecuJes; as an illustration of this, H-D. Volk (Berlin) showed data demonstrating that in patients with septicemia there is a dose association between re- duction in monocyte HLA-DR ex- pression and fatal outcome. MHC antigen expression is modu- lated by T-cell-derived cytokines but can also be profoundly influenced by the natural resistance gene Beg (which is probably identical to lty and Lsh). Beg is located on mouse chromosome 1 and, presumably, on human chromosome 2q, within a set of genes coding for cytoskeletal pro- teins (E. Skarnene, Montreal). In its two allelic forms Beg confers resist- ance and susceptibility to infee- tion with Salmonella typhimurium, Leishmania donovani, mycobacteria and other macrophagic parasites in mice and preliminary studies in humans suggest a similar dichot- omy. The Beg gene product, in ad- dition to controlling MHC dass 11 antigen expression, affects 5' nu- deotidase activation, the respiratory burst and expression of the ligand for AcM.l, an antibody that recog- nizes activated macrophagcs. MHC molecules direct the im- mune system towards responses me- dia ted largely by either CD4 + or CD8+ T cells and this may be partly