ETH Zürich, Switzerland

An infection biologist points out an outstanding issue in mucosal immunology.

The gut immune system can distinguish between harmless commensal microorganisms and dangerous pathogens, and attenuates its response to the former to avoid dangerous chronic inflammation. The mechanisms that maintain this hyporesponsiveness are just beginning to be unravelled.

Dendritic cells, the key organizers of appropriate immune responses, actively sample commensal microbes. In organs other than the gut, this would trigger a strong immune response, and the responsiveness of intestinal dendritic cells to microbes is thought to be thwarted by anti-inflammatory molecules released by gut cells. But the situation could be much more complex: hyporesponsiveness might be restricted to certain 'microbe-associated molecular patterns' (MAMPs), such as lipopolysaccharides, large molecules attached to the outer membrane of many bacteria.

Linda Klavinskis of Kings College London and her team have analysed the MAMP-responsiveness of dendritic cells migrating from gut tissue to local lymph nodes. Surprisingly, these cells do respond to harmless Bacillus spores and most MAMPs — but not lipopolysaccharides (V. Cerovic et al. J. Immunol. 182, 2405–2415; 2009). Does this suggest that hyporesponsiveness of intestinal dendritic cells is transient? The maintenance of hyporesponsiveness in the gut mucosa, patterns of MAMP-hyporesponsiveness, and localization and timing of MAMP responses will be important topics for future research.

Unfortunately, unactivated dendritic cells are hard to isolate from the gut mucosa. In situ analysis of dendritic-cell responses to gut microbes in intact tissue holds much promise. Technical advances in multicolour two-photon microscopy, fluorescently tagged microbes, and transgenic mice expressing cell-type and response-specific fluorescent reporter proteins will be instrumental in this key area of biology.