For paramedics to provide life-saving treatment for people involved in car accidents, the ambulance driver needs to ensure their safe arrival at the site of the crash by following road signs and signals. In the same way, for a protective cellular immune response to infection by Mycobacterium tuberculosis, macrophages and T cells need to be rapidly recruited to the lung. The signals that guide these cells to the site of infection have, until now, been unknown. Recent work, published in Proceedings of the National Academy of Sciences by Peters and colleagues, shows that the C-C chemokine receptor 2 (CCR2) is essential in these processes.

Chemokines are low-molecular-mass chemotactic cytokines that control leukocyte migration and activation. Mice that are deficient for certain chemokine receptors, including CCR2 (the receptor for monocyte chemoattractant proteins), show defects in leukocyte migration to sites of inflammation. Here, the authors used CCR2-deficient mice to investigate the role of this receptor in resistance to M. tuberculosis.

When infected with M. tuberculosis, the CCR2−/− mice had a rapid and fatal course of infection, and had 100-fold more bacteria in their lungs than wild-type mice. Early after infection, the CCR2−/− mice showed a defect in the recruitment of macrophages and a later defect in the recruitment of dendritic cells and T cells into the lung.

Macrophages have been implicated in the transport of phagocytosed particles from the lung to the lymph nodes, an essential process for the generation of a cellular immune response. So, Peters and co-workers next asked whether this defect in macrophage recruitment to the lungs might result in fewer macrophages (which bear M. tuberculosis antigens) reaching the draining lymph nodes, resulting in defective priming of T cells in the CCR2−/− mice. The CCR2−/− mice had fewer macrophages and dendritic cells recruited to these lymph nodes after infection and, although T-cell migration through the lymph nodes was normal in these mice, T-cell priming was delayed. Following on from this, the authors also showed that fewer T cells expressing the CD4 and CD8 cells were primed to produce interferon-γ — and, therefore, a protective response — were present in the lungs of the CCR2−/− mice.

Although previous work has demonstrated a role for CCR2 in leukocyte recruitment to sites of inflammation, this is the first demonstration of the importance of CCR2-dependent cell recruitment in the protective response to M. tuberculosis. The authors conclude that these findings have important implications for human disease. CCR2 antagonists are being developed for use as treatment for anti-inflammatory diseases. These results indicate that increased susceptibility to intracellular pathogens, such as M. tuberculosis, might be a possible side effect of the long-term use of such antagonists.