Lung dendritic cells imprint T cell lung homing and promote lung immunity through the chemokine receptor CCR4

T cell trafficking into the lung is critical for lung immunity, but the mechanisms that mediate T cell lung homing are not well understood. Here, we show that lung dendritic cells (DCs) imprint T cell lung homing, as lung DC–activated T cells traffic more efficiently into the lung in response to inhaled antigen and at homeostasis compared with T cells activated by DCs from other tissues. Consequently, lung DC–imprinted T cells protect against influenza more effectively than do gut and skin DC–imprinted T cells. Lung DCs imprint the expression of CCR4 on T cells, and CCR4 contributes to T cell lung imprinting. Lung DC–activated, CCR4-deficient T cells fail to traffic into the lung as efficiently and to protect against influenza as effectively as lung DC–activated, CCR4-sufficient T cells. Thus, lung DCs imprint T cell lung homing and promote lung immunity in part through CCR4.CD4⁺ T cells orchestrate the recruitment and subsequent activation of innate and adaptive immune cells in the tissue through the production of cytokines and critically contribute to the generation of a robust immune response to invading pathogens (Reinhardt et al., 2006). A prerequisite for CD4⁺ T cell participation in host defense is their recruitment into peripheral nonlymphoid tissue both in response to pathogens and at homeostasis so that antigen-experienced T cells are positioned where pathogen reencounter is most likely to occur. The mechanisms that govern this strategic distribution of T cells into tissues are not fully defined.Organs with large epithelial surfaces such as the gut and the skin are in constant contact with the environment and are exposed to potential pathogens on a regular basis and therefore need an efficient immune response strategy to prevent infections at these sites. The unique structure and function of each organ determine its exposures and vulnerabilities to specific pathogens and make reexposure to a particular pathogen more likely in the same organ. For example, by virtue of its ecology, the gut is susceptible to infection with Salmonella and Shigella, organisms which are not pathogens in the skin. To streamline T cell memory immune responses based on the predictability of pathogen reexposure, the gut and the skin have evolved tissue-selective T cell imprinting, a process whereby DCs derived from the gut instruct T cells to home preferentially into the gut, whereas DCs derived from the skin instruct T cells to preferentially home into the skin. Gut DCs imprint the expression of α4β7 and CCR9 on T cells, and in doing so enable their entry into the small intestine in response to intestinal MAdCAM-1 and CCL25, respectively (Stagg et al., 2002; Johansson-Lindbom et al., 2003; Mora et al., 2003). Similarly, skin-derived DCs imprint T cell expression of P- and E-selectin ligands and CCR10, allowing T cell skin homing via cutaneous P- and E-selectins and CCL27, respectively (Campbell and Butcher, 2002; Dudda et al., 2004; Sigmundsdottir et al., 2007). This may explain why peripheral blood memory T cells that proliferate in response to rotavirus, a gut pathogen, are α4β7⁺ (Rott et al., 1997), whereas peripheral blood T cells specific for herpes simplex virus 2, a skin tropic virus, express high levels of CLA (Koelle et al., 2002). The unique structure and function of each organ also offer a distinct set of tissue-specific autoantigens, such that the autoantigens generated in the intestine would be different from those generated in the skin. Therefore, tissue-selective T cell imprinting might have also evolved to enable tissue-specific regulatory T cells to home efficiently to the location of their autoantigens.Tissue-selective T cell imprinting was described a decade ago for the gut and the skin and to date has not been shown for any other organ, raising the possibility that it might be a phenomenon restricted to these two organs. Like the gut and the skin, however, the lung is a large epithelial organ in continuous contact with the environment and potential pathogens. The lung also has its own unique structure and function, specific pathogen susceptibility (i.e., pneumococcus and influenza), and autoantigens and thus is poised to benefit from tissue-selective T cell imprinting. Understanding whether lung DCs imprint T cell lung homing is fundamental to understanding T cell immunity to inhaled antigens and pathogens. Whether lung DCs instruct T cells to home to the lung has implications for vaccine development and potentially opens novel therapeutic approaches for a variety of inflammatory T cell–mediated lung diseases. Here, we sought to determine whether lung DCs imprint T cell lung homing and, if so, the impact of lung imprinting on lung immunity.