Impact of regulatory dendritic cells in neonatal immune responses to Influenza infection

About This Grant

Abstract Respiratory viral infections (RVI) are a burden for society since they produce short- and long-term sequelae that impair the lung function. The impact of RVI is enhanced in newborns and young infants since their immune system is defective in generating protective CD8 T cell responses. Our published work in Science Immunology described a new form of XCR1+ dendritic cell maturation that impair the differentiation of IFNg effector cells in neonatal lungs. This form of regulatory cDC1 maturation (mregDC1) depends on the recognition of apoptotic cells and unlike proinflammatory cDC1, mregDC1 do not require TLR or microbiota for their maturation. In non- infected mice, the pulmonary mregDC1 is abundant during the first 14 days of life, suggesting that the increased susceptibility to RVIs in neonates is caused by mregDC1 differentiation (our central hypothesis). Due to their novelty, the role of mregDC1 in the neonatal immune responses against neonatal RVI has not been studied. To answer this question (Aim 1), we have generated two unique mouse strains with genetic deletions affecting only the cDC1 lineage and mregDC1 differentiation. Using these mice and in the context of Influenza A virus (IAV) infection, we will study whether mregDC1 protect the neonatal lung from inflammation at the expense of the ability to control IAV, whether T cells primed by mregDC1 are forced into a memory-like phenotype, and whether lacking mregDC1 during IAV infection carries a risk of breaking peripheral tolerance. Although the cDC1 lineage specializes in CD8 T cell activation, they can also present antigens in MHC-II molecules and interact with CD4 T cells. In aim 2.1 we will characterize the transcriptomic program induced in CD4 T cells by mregDC1, we expect to find a previously unknow way to induce anti-inflammatory functions in CD4 T cells. Finally, in mice and humans mregDCs have the capacity to induce changes in stromal cells. In mice mregDC1 alter the lymph node endothelial and fibroblastic reticular cells, while in human adults, mregDCs can induce the formation of tertiary lymphoid structures in the lungs. In aims 2.2 (mice) and 3 (human infants), we will perform spatial proteomic analysis of the mregDC1 – lung stromal cell interactions and study the structural changes to the lungs in the absence of mregDC1 (aim 2.2) or changes to mregDC1 development when alveolarization is interrupted (aim 3.1). Overall, our proposal will define the role of mregDC1 in promoting postnatal lung development while protecting the neonatal lungs from RVI and T cell mediated inflammation.