Dendritic cells (DCs) are antigen-presenting cells that play an essential role in mucosal tolerance. They regularly encounter beneficial intestinal bacteria, but the nature of these cellular contacts and the immune responses elicited by the bacteria are not entirely elucidated. Here, we examined the interactions of Lactobacillus acidophilus NCFM and its cell surface compounds with DCs. L. acidophilus NCFM attached to DCs and induced a concentration-dependent production of IL-10, and low IL-12p70. We further demonstrated that the bacterium binds to DC-specific ICAM-3-grabbing nonintegrin (DC-SIGN), a DC- specific receptor. To identify the DC-SIGN ligand present on the bacterium, we took advantage of a generated array of L. acidophilus NCFM mutants. A knockout mutant of L. acidophilus NCFM lacking the surface (S) layer A protein (SlpA) was significantly reduced in binding to DC-SIGN. This mutant incurred a chromosomal inversion leading to dominant expression of a second S layer protein, SlpB. In the SlpB-dominant strain, the nature of the interaction of this bacterium with DCs changed dramatically. Higher concentrations of proinflammatory cytokines such as IL-12p70, TNFα, and IL-1β were produced by DCs interacting with the SlpB-dominant strain compared with the parent NCFM strain. Unlike the SlpA-knockout mutant, T cells primed with L. acidophilus NCFM stimulated DCs produced more IL-4. The SlpA–DC-SIGN interaction was further confirmed as purified SlpA protein ligated directly to the DC-SIGN. In conclusion, the major S layer protein, SlpA, of L. acidophilus NCFM is the first probiotic bacterial DC-SIGN ligand identified that is functionally involved in the modulation of DCs and T cells functions.

Neutrophils are key players of the innate immune system that provide a first line of defense against invading pathogens. However, it is unknown whether neutrophils can interact with dendritic cells (DCs) to modulate adaptive immune responses. We demonstrate that neutrophils strongly cluster with immature DCs and that activated, not resting, neutrophils induce maturation of DCs that enables these DCs to trigger strong T cell proliferation and T helper type 1 polarization of T cells. This neutrophil–DC interaction is driven by the binding of the DC-specific, C-type lectin DC-SIGN to the β₂-integrin Mac-1. Strikingly, DC-SIGN only interacts with Mac-1 from neutrophils, but not from other leukocytes, mainly because of specific Lewis^x carbohydrates that are present on the α_M chain of Mac-1 from neutrophils. Furthermore, we show that besides the formation of cellular contact, the tumor necrosis factor-α produced by activated neutrophils is essential for inducing DC maturation. Our data demonstrate that DC-SIGN and Mac-1 define a molecular pathway to establish cellular adhesion between DCs and neutrophils, thereby providing a novel cellular link between innate and adaptive immunity.

In recent years, many paradigms concerning central nervous system (CNS) immunology have been challenged and shifted, including the discovery of CNS-draining lymphatic vessels, the origin and functional diversity of microglia, the impact of T cells on CNS immunological homeostasis and the role of neuroinflammation in neurodegenerative diseases. In parallel, antigen presentation outside the CNS has revealed the vital role of antigen-presenting cells in maintaining tolerance toward self-proteins, thwarting auto-immunity. Here, we review recent findings that unite these shifted paradigms of microglial functioning, antigen presentation, and CNS-directed T cell activation, focusing on common neurodegenerative diseases. It provides an important update on CNS adaptive immunity, novel targets, and a concept of the microglia T-cell equilibrium.

Changes in glycosylation during tumour progression are a key hallmark of cancer. One of the glycan moieties generally overexpressed in cancer are sialic acids, which can induce immunomodulatory properties via binding to Siglec receptors. We here show that Pancreatic Ductal Adenocarcinoma (PDAC) tumour cells present an increased sialylation that can be recognized by Siglec-7 and Siglec-9 on myeloid cells. We identified the expression of the α2,3 sialyltransferases ST3GAL1 and ST3GAL4 as main contributor to the synthesis of ligands for Siglec-7 and Siglec-9 in tumour cells. Analysing the myeloid composition in PDAC, using single cell and bulk transcriptomics data, we identified monocyte-derived macrophages as contributors to the poor clinical outcome. Tumour-derived sialic acids dictate monocyte to macrophage differentiation via signalling through Siglec-7 and Siglec-9. Moreover, triggering of Siglec-9 in macrophages reduce inflammatory programmes, while increasing PD-L1 and IL-10 expression, illustrating that sialic acids modulate different myeloid cells. This work highlights a critical role for sialylated glycans in controlling immune suppression and provides new potential targets for cancer immunotherapy in PDAC.