Bujko et al. describe four distinct subsets of macrophages in human small intestine that are completely replaced in transplanted duodenum. These subsets show graduated changes in their phenotypes, function, and transcriptome profiles, suggesting that they represent stages of monocyte-derived macrophage maturation in tissue.

This study provides a definite answer to the long-standing question concerning the longevity of the secretory antibody response. Landsverk et al. show that antigenic attrition affects a minor plasma cell subset and that distinct plasma cells are likely maintained for life in the human small intestine.

Resident memory CD8 T (Trm) cells have been shown to provide effective protective responses in the small intestine (SI) in mice. A better understanding of the generation and persistence of SI CD8 Trm cells in humans may have implications for intestinal immune-mediated diseases and vaccine development. Analyzing normal and transplanted human SI, we demonstrated that the majority of SI CD8 T cells were bona fide CD8 Trm cells that survived for >1 yr in the graft. Intraepithelial and lamina propria CD8 Trm cells showed a high clonal overlap and a repertoire dominated by expanded clones, conserved both spatially in the intestine and over time. Functionally, lamina propria CD8 Trm cells were potent cytokine producers, exhibiting a polyfunctional (IFN-γ+ IL-2+ TNF-α+) profile, and efficiently expressed cytotoxic mediators after stimulation. These results suggest that SI CD8 Trm cells could be relevant targets for future oral vaccines and therapeutic strategies for gut disorders.

No abstract

Background & aims: The pathogenesis of celiac disease (CD) is thought to be driven by a transglutaminase 2 (TG2)-dependent inflammatory CD4 + T-cell response in the gut towards deamidated gluten peptides in the context of disease-associated HLA-DQ molecules. We aimed to gain insight into the antigen presentation process underlying this mucosal immune response. Methods: We generated monoclonal antibodies (mAbs) specific for the peptide-MHC (pMHC) complex HLA-DQ2.5 and the immunodominant gluten epitope DQ2.5-glia-α1a using phage display. Using these mAbs we assessed gluten peptide presentation in freshly prepared single-cell suspensions of patient intestinal biopsies. Results: The mAbs allowed specific detection of in vivo generated pMHC complexes on the cells of gut biopsies from CD patients consuming gluten. Surprisingly, we identified B cells and plasma cells (PCs) as the most abundant cells presenting DQ2.5-glia-α1a in the inflamed mucosa. Further, we demonstrate that a group of these PCs expresses B-cell receptors (BCRs) specific for either gluten peptides or the autoantigen TG2. MHC class II (MHCII) expression was not restricted to these specific PCs associated with CD, but was observed at an average of 30% of the gut PCs both in CD patients as well as in non-inflamed tissue. Conclusions: A population of PCs in the gut expresses MHCII and is the most abundant cell type presenting the immunodominant gluten peptide DQ2.5-glia-α1a. These results suggest an important and previously unappreciated role of PCs in the gut as antigen presenting cells (APCs). PCs may thus be responsible for promoting and sustaining intestinal inflammation such as in CD.

SN provided incremental prognostic information to established risk indices in acute HF and ventricular arrhythmia-induced cardiac arrest.

Since its discovery in the late 1970s [1], the invariant chain (Ii) molecule has been attributed an increasing number of properties related to Major Histocompatibility Complex (MHC) class II (MHC II) antigen presentation and beyond. The examination into the structural and functional properties of this molecule is, however, by no means exhausted, and to this day studies featuring Ii are published on a regular basis. Here we attempt to give an overview of the current knowledge about MHC II trafficking and the endomembrane system in relation to MHC II peptide loading and presentation. A special focus will be given to the versatile Ii molecule. Structure of MHC II and IiWhereas MHC class I (MHC I) is ubiquitously expressed on all nucleated cells, the expression of MHC II is generally restricted to a limited set of cells, which include cells of the monocyte-macrophage lineage (Mhs), dendritic cells (DCs) and B lymphocytes. These three constitute the so-called professional antigen presenting cells (APCs), and are more or less specialized to acquire, process and present antigens. In humans (but not in mice) activated T cells can also express MHC II, and thymic epithelial cells ( MHC II is encoded by polymorphic genes and expressed as non-covalent heterodimers of two type I (N-terminal in lumen, C-terminal in cytosol) transmembrane (TM) polypeptides. The a (35 kDa) and the b (28 kDa) chain differ in size mainly due to difference in N-linked glycosylation [5]. The luminal domains of the MHC II chains have an intrinsic ability to associate [6,7], but interactions by the TM domains promote the formation of correctly assembled complexes [8]. The extracellular part of the MHC II molecule forms a groove composed of two a-helices supported by an eight-strand b-pleated sheet. The groove contains pockets into which anchoring peptide side chains can fit, and is open at the ends, allowing peptides of varying length to bind. In humans, there are three pairs of polymorphic MHC II genes, named human leukocyte antigen (HLA)-DR, -DP and -DQ (hereafter DR, DP and DQ) [9], and two pairs of non-classical MHC II genes, HLA-DM (DM) [10] and HLA-DO (DO) [11]. The genes are clustered on the short arm (q) of chromosome 6, one of the most gene-rich regions in mammalian genomes [12]. In the murine system, two major groups of the MHC II genes exist, I-A and I-E, as well as the non-classical genes encoding H-2M and H-2O. The Ii gene is located on human chromosome 5 (q32), and was first identified in 1979 by Jones et al. AbstractThe major histocompatibility complex (MHC) class I and II molecules perform vital functions in innate and adaptive immune responses towards invading pathogens. MHC class I molecules load peptides in the endoplasmatic reticulum (ER) and display them to the T cell receptors (TcR) on CD8 + T lymphocytes. MHC class II molecules (MHC II) acquire their peptides in endosomes and present these to the TcR on CD4+ T lymphocytes. They are vital for the generation of humoral immune responses. MHC II assembly in the ER and trafficking ...

The tissue dendritic cell (DC) compartment is heterogeneous, and the ontogeny and functional specialization of human tissue conventional DC (cDC) subsets and their relationship with monocytes is unresolved. Here we identify monocyte-related CSF1RFlt3 antigen presenting cells (APCs) that constitute about half of the cells classically defined as SIRPα DCs in the steady-state human small intestine. CSF1RFlt3 APCs express calprotectin and very low levels of CD14, are transcriptionally related to monocyte-derived cells, and accumulate during inflammation. CSF1RFlt3 APCs show typical macrophage characteristics functionally distinct from their Flt3 cDC counterparts: under steady-state conditions they excel at antigen uptake, have a lower migratory potential, and are inefficient activators of naïve T cells. These results have important implications for the understanding of the ontogenetic and functional heterogeneity within human tissue DCs and their relation to the monocyte lineage.