Mucosal Immunity

The role of the maternal immune system in reproductive success in humans remains controversial. Here we focus on the events that occur in the maternal decidua during the first few weeks of human pregnancy, because this is the site at which maternal leukocytes initially interact with and can recognize fetal trophoblast cells, potentially involving allorecognition by both T cells and natural killer (NK) cells. NK cells are the dominant leukocyte population in first-trimester decidua, and genetic studies point to a role of allorecognition by uterine NK cells in establishing a boundary between the mother and the fetus. By contrast, definitive evidence that allorecognition by decidual T cells occurs during the first trimester is lacking. Thus, our view is that during the crucial period when the placenta is established, damaging T cell-mediated adaptive immune responses towards placental trophoblast are minimized, whereas NK cell allorecognition contributes to successful implantation and healthy pregnancy. Major human pregnancy disorders arise from the failure of placental trophoblast to access sufficient supplies of maternal oxygen and nutrients. Key to understanding this process are the interactions that occur early in pregnancy between trophoblast cells that invade the decidua and maternal uterine immune cells.

Single-cell transcriptomics has allowed unprecedented resolution of cell types/states in the human lung, but their spatial context is less well defined. To (re)define tissue architecture of lung and airways, we profiled five proximal-to-distal locations of healthy human lungs in depth using multi-omic single cell/nuclei and spatial transcriptomics (queryable at lungcellatlas.org ). Using computational data integration and analysis, we extend beyond the suspension cell paradigm and discover macro and micro-anatomical tissue compartments including previously unannotated cell types in the epithelial, vascular, stromal and nerve bundle micro-environments. We identify and implicate peribronchial fibroblasts in lung disease. Importantly, we discover and validate a survival niche for IgA plasma cells in the airway submucosal glands (SMG). We show that gland epithelial cells recruit B cells and IgA plasma cells, and promote longevity and antibody secretion locally through expression of CCL28, APRIL and IL-6. This new ‘gland-associated immune niche’ has implications for respiratory health. Multi-omics profiling of 45 human lung samples highlights 80 different cell types along the proximal to distal axis of the lung with certain cell types showing enrichment for disease-associated genes. An immune niche for IgA-expressing plasma cells within airway submucosal glands (SMG) is also identified.

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The nasal cavity is a primary checkpoint for the invasion of respiratory pathogens. Numerous pathogens, including SARS-CoV-2, S. pneumoniae, S. aureus, etc., can adhere/colonize nasal lining to trigger an infection. Secretory IgA (sIgA) serves as the first line of immune defense against foreign pathogens. sIgA facilitates clearance of pathogenic microbes by intercepting their access to epithelial receptors and mucus entrapment through immune exclusion. Elevated levels of neutralizing IgA at the mucosal surfaces are associated with a high level of protection following intranasal immunizations. This review summarizes recent advances in intranasal vaccination technology and challenges in maintaining nominal IgA levels at the mucosal surface. Overall, the review emphasizes the significance of IgA-mediated nasal immunity, which holds a tremendous potential to mount protection against respiratory pathogens.

Macrophage migration inhibitory factor (MIF) is a key innate immune mediator with chemokine- and cytokine-like properties in the inflammatory pathway. While its actions on macrophages are well-studied, its effects on other cell types are less understood. Here we report that MIF is required for expansion of intestinal tuft cells during infection with the helminth Nippostrongylus brasiliensis. MIF-deficient mice show defective innate responses following infection, lacking intestinal epithelial tuft cell hyperplasia or upregulation of goblet cell RELMβ, and fail to expand eosinophil, type 2 innate lymphoid cell (ILC2) and macrophage (M2) populations. Similar effects were observed in MIF-sufficient wild-type mice given the MIF inhibitor 4-IPP. MIF had no direct effect on epithelial cells in organoid cultures, and MIF-deficient intestinal stem cells could generate tuft cells in vitro in the presence of type 2 cytokines. In vivo the lack of MIF could be fully compensated by administration of IL-25, restoring tuft cell differentiation and goblet cell expression of RELM-β, demonstrating its requirement upstream of the ILC2-tuft cell circuit. Both ILC2s and macrophages expressed the MIF receptor CXCR4, indicating that MIF may act as an essential co-factor on both cell types to activate responses to IL-25 in helminth infection.

Mucosal immunity has a pivotal role in protection from respiratory viral infections.1
The current authors have showed substantial protection from omicron infection by high
concentrations of nasal mucosal SARS-CoV-2 WT spike immunoglobulin-A (M-IgA) over
a 4-week screening period.2 A sharp increase in M-IgA concentrations following BA.1
or BA.2 breakthrough infection in triple vaccinated health-care workers was also observed.2
Here, we present follow-up data with prospectively collected omicron infection rates
and systemic and mucosal antibody concentrations from the same cohort (appendix pp
7–9, 12–14).