LAUSR

Allergic airway inflammation is driven largely by Th2 (type 2 T helper) cells. Although these cells were first identified more than 3 decades ago (1), much remains to be learned of the molecular mechanisms that drive Th2 generation. It is well established that dendritic cells (DCs), the potent antigen-presenting cells that reside in most tissues, can promote the differentiation of naive CD4 T cells to effector T cells, including Th1, Th2, Th17, and regulatory T (Treg) cells (2). Many of the cytokines that drive these differentiation events have been characterized and are produced by DCs or microenvironmental bystander cells (3, 4). IL-12 (Th1), IL-1b, and IL-6 (Th17), and TGF-b and retinoic acid (Tregs) are all produced by DCs. By contrast, the cytokines required for Th2 differentiation, IL-2 and IL-4, are not produced by DCs (2–4). IL-2 and IL-4 are produced by CD4 T cells immediately after DC priming, and it has therefore been unclear whether DCs provide specific signals that promote Th2 polarization or if naive CD4 T cells default to Th2 differentiation in the absence of polarizing cytokines (3). Recent evidence suggests that in some tissues, specific DC subsets preferentially promote Th2 differentiation. For example, Kumamoto and colleagues demonstrated that CD301b dermal DCs, a subset among type 2 conventional DCs (cDC2s), potently stimulate Th2 differentiation (5). Tussiwand and colleagues found that transcription factor KLF4-dependent CD11b cDC2s, a unique DC subset in the skin, is required for Th2 cell differentiation (6). Very recently, Mayer and colleagues showed that the development of Th2-inducing CD11b cDC2s is dependent on IL-13 derived from type 2 innate lymphoid cells in the skin (7). These studies have made important contributions to our general knowledge of DC subsets required for Th2 immunity. However, CD11b cDC2s are very rare in the lung and lungdraining lymph nodes, and the Th2-inducing capacity of lung DCs is not dependent on signal transducer and activator of transcription (STAT)-6 or IL-13. This suggests that the mechanism of action for Th2-inducing cells in the lung differs from that of their counterparts in the skin (7). In theory, the identification of lung DC subsets that strongly induce Th2 cells in the airway should provide clues to their molecular mechanisms of action. However, a consensus Th2inducing DC subset in the lung has not yet been firmly established. For example, whereas one study reported that RELB-dependent lung CD117 cDC2s promote Th2 responses and allergic airway inflammation (8), a different study reported a suppressive role of RELB in type 2 airway inflammation (9). Single-cell RNA sequencing of lung DCs should help to resolve such apparent inconsistencies, and Izumi and colleagues recently reported that the CD200 lung cDC2 subset preferentially stimulates Th2 differentiation (10). In the current issue of the Journal, Aono and colleagues (pp. 201–212) report that CD109 lung cDC2s are sufficient for the induction of Th2 differentiation and allergic airway inflammation and that CD109 on cDC2s is required for priming Th2 immunity (11). They found that CD109 protein is not displayed on lung DCs at steady state, but it is induced in a cDC2 subset on house dust mite inhalation. CD109 cDC2s have a mature phenotype, display high concentrations of CD80, PD-L1, and ICOS-L, and take up larger amounts of antigen than CD109 cDC2s. Importantly, antigenloaded CD109 cDC2s activated CD4 T cells in vitromore potently than did CD109 cDC2s. Adoptive transfer of allergen-bearing CD109 cDC2s generated from bone marrow also strongly primed Th2 immunity and allergic airway inflammation on their transfer into recipient mice, whereas CD109-deficient DCs did so only weakly. Furthermore, blockade of CD109 by monoclonal antibody injection suppressed airway inflammation in house dust mite-induced mouse model asthma. This demonstration of a specific molecule on DCs that promotes Th2 immunity is exciting and raises the intriguing possibility that CD109 could be a potential therapeutic target in asthma. Although this new study by Aono and colleagues has demonstrated the role of CD109 in allergic airway inflammation, the molecular mechanisms of CD109-mediated T-cell activation remain unclear. It is notable that in addition to having impaired Th2 responses, Cd109 cDC2s also failed to efficiently prime Th1 and Th17 differentiation and had a reduced ability to promote T-cell proliferation (11). Thus, CD109 might be important for antigen uptake and general T-cell activation, as opposed to having a more restricted role in Th2 cell polarization. Another caveat to their report is that Cd109 is expressed by a wide variety of cell types, including epithelial cells, endothelial cells, platelets, and T cells (12, 13). As the authors used whole-body Cd109 knockout mice, as opposed to DC-specific mutant mice, it is possible that the absence of Cd109 in cells other than DCs contributed to the observed phenotype. This potential concern is somewhat mitigated, however, by the authors’ demonstration that adoptively transferred Cd109 cDC2s were less efficient at priming Th2 immunity in vivo than were their Cd109 cDC2 counterparts. Likely mechanisms for CD109 action in DCs involve the regulatory cytokine, TGF-b, which suppresses T-cell proliferation and induces Treg differentiation. CD109 is a glycosylphosphatidylinositol (GPI)-anchored glycoprotein enriched in lipid rafts and binds to TGF-b receptors (13). As TGF-b suppresses antigen-presenting cell function of DCs (14), cell surface CD109 on DCsmight enhance their potency by reversing the TGF-b–mediated suppression. Furthermore,