Expression on Inflammatory Dendritic Cells Regulates CD4 T Cell Cytokine Production in the Lung during Viral Disease

CD4 Th differentiation is influenced by costimulatory molecules expressed on conventional dendritic cells (DCs) in regional lymph nodes and results in specific patterns of cytokine production. However, the function of costimulatory molecules on inflammatory (CD11b +) DCs in the lung during recall responses is not fully understood, but it is important for development of novel interventions to limit immunopathological responses to infection. Using a mouse model in which vaccination with vaccinia virus vectors expressing the respiratory syncytial virus (RSV) fusion protein (rVVF) or attachment protein (rVVG) leads to type 1-or type 2-biased cytokine responses, respectively, upon RSV challenge, we found expression of CD40 and OX40 ligand (OX40L) on lung inflammatory DCs was higher in rVVF-primed mice than in rVVG-primed mice early after RSV challenge, whereas the reverse was observed later in the response. Conversely, programmed cell death 1 ligand 2 (PD-L2) was higher in rVVG-primed mice throughout. Inflammatory DCs isolated at the resolution of inflammation revealed that OX40L on type 1-biased DCs promoted IL-5, whereas OX40L on type 2-biased DCs enhanced IFN-g production by Ag-reactive Th cells. In contrast, PD-L2 promoted IFN-g production, irrespective of conditions, suppressing IL-5 only if expressed on type 1-biased DCs. Thus, OX40L and PD-L2 expressed on DCs differentially regulate cytokine production during recall responses in the lung. Manipulation of these costimulatory pathways may provide a novel approach to controlling pulmonary inflammatory responses. U pon respiratory viral challenge, conventional lung den-dritic cells (DCs) mature and migrate to the regional lymph nodes where they present Ag in the context of MHC to naive Ag-specific T cells (1–3). During this period of activation , naive CD4 T cells are educated to become Th1, Th2, Th17, or regulatory T cells (Tregs) or remain part of a large uncommitted population (Th0) that can become polarized at a later stage (4). It now seems that polarization is reversible and that both human and mouse Th1 and Th2 cells maintain flexibility and can respond to alternative polarizing conditions (5–7). These conditions consist of a combination of cytokines and costimulatory signals typically provided by APCs, in particular conventional DCs (5–7). In models of allergic airway inflammation, DCs were shown to be required to initiate, as well as maintain, recall T cell responses (8). Many costimulatory molecules expressed by DCs have been shown to be important in regulating T cells during both primary and recall responses. There is evidence that cytokine production by effector …