Lung DCs that lack IL-12p40 fail to migrate to lymph nodes in response to challenge with Mtb.

When airborne bacteria are inhaled into the lungs they are quickly taken up by resident dendritic cells (DCs), which ferry bacterial antigens to the lymph nodes. Once in the lymph node, DCs produce interleukin (IL)-12p70 to help activate bug-specific T helper (Th)-1 cells. According to Khader and colleagues on page 1805, DCs also use homodimers of the p40 subunit of IL-12p70 to help them embark on their journey from lung to lymph node.

The production of bioactive IL-12p70—which is composed of p40 and p35 subunits—is required for protection against Mycobacterium tuberculosis (Mtb) infection in both mice and men. Without IL-12p35 and p40, protective Th1 cells are not activated and bacterial growth goes unchecked.

Mice expressing only p40, however, fare better than those lacking both subunits, despite their inability to produce bioactive IL-12p70. This survival advantage is in part because p40 is one half of yet another Th-1–promoting cytokine (IL-23). Now, Khader et al. show that p40 homodimers also trigger the migration of Mtb-exposed DCs from the lung to the lymph nodes. This finding may help explain the observation that p40 alone is produced early and in high amounts in several models of lung inflammation, even though it blocks IL-12p70 signaling.

Only DCs that express p40 were able to respond to the chemokines CCL19 and CCL21, which normally coax DCs into the lymph nodes. DCs lacking p40 produced excess IL-10, which might explain their ambivalence to chemokines as IL-10 was recently shown to short-circuit chemokine receptor signaling in human DCs and monocytes.