As the professional antigen-presenting cells of the immune system, dendritic cells (DCs) sense the microenvironment and shape the ensuing adaptive immune response. DCs can induce both immune activation and immune tolerance according to the peripheral cues. Recent work has established that DCs comprise of several phenotypically and functionally heterogeneous subsets that differentially regulate T lymphocyte differentiation. This review summarizes both mouse and human DC subset phenotypes, development, diversification, and function. We focus on advances in our understanding of how different DC subsets regulate distinct CD4+ T helper (Th) cell differentiation, including Th1, Th2, Th17, T follicular helper, and T regulatory cells. We review DC subset intrinsic properties, local tissue microenvironments, and other immune cells that together determine Th cell differentiation during homeostasis and inflammation. Expected final online publication date for the Annual Review of Immunology, Volume 39 is April 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

There are three major dendritic cell (DC) subsets in both humans and mice, that is, plasmacytoid DCs and two types of conventional DCs (cDCs), cDC1s and cDC2s. cDC2s are important for polarizing CD4 naive T cells into different subsets, including Th1, Th2, Th17, Th22, and regulatory T cells. In mice, cDC2s can be further divided into phenotypically and functionally distinct subgroups. However, subsets of human cDC2s have not been reported. In the present study, we showed that human blood CD1c cDCs (cDC2s) can be further separated into two subpopulations according to their CD5 expression status. Comparative transcriptome analyses showed that the CD5 DCs expressed higher levels of cDC2-specific genes, including IFN regulatory factor 4, which is essential for the cDC2 development and its migration to lymph nodes. In contrast, CD5 DCs preferentially expressed monocyte-related genes, including the lineage-specific transcription factor MAFB. Furthermore, compared with the CD5 subpopulation, the CD5 subpopulation showed stronger migration toward CCL21 and overrepresentation among migratory DCs in lymph nodes. Additionally, the CD5 DCs induced naive T cell proliferation more potently than did the CD5 DCs. Moreover, CD5 DCs induced higher levels of IL-10-, IL-22-, and IL-4-producing T cell formation, whereas CD5 DCs induced higher levels of IFN-γ-producing T cell formation. Thus, we show that human blood CD1c cDC2s encompass two subsets that differ significantly in phenotype, that is, gene expression and functions. We propose that these two subsets of human cDC2s could potentially play contrasting roles in immunity or tolerance.

Rab31, a protein that we originally cloned from a rat oligodendrocyte cDNA library, localizes in the trans Golgi network (TGN) and endosomes. However, its function has not yet been established. Here we show the involvement of Rab31 in the transport of mannose 6-phosphate receptors (MPRs) from TGN to endosomes. We demonstrate the specific sorting of cation-dependent-MPR (CD-MPR), but not CD63 and vesicular stomatitis virus G (VSVG) protein, to Rab31-containing trans-Golgi network carriers. CD-MPR and Rab31 containing carriers originate from extending TGN tubules that also contain clathrin and GGA1 coats. Expression of constitutively active Rab31 reduced the content of CD-MPR in the TGN relative to that of endosomes, while expression of dominant negative Rab31 triggered reciprocal changes in CD-MPR distribution. Expression of dominant negative Rab31 also inhibited the formation of carriers containing CD-MPR in the TGN, without affecting the exit of VSVG from this compartment. Importantly, siRNA-mediated depletion of endogenous Rab31 caused collapse of the Golgi apparatus. Our observations demonstrate that Rab31 is required for transport of MPRs from TGN to endosomes and for the Golgi/TGN organization.

Food allergy now affects 6%–8% of children in the Western world; despite this, we understand little about why certain people become sensitized to food allergens. The dominant form of food allergy is mediated by food-specific immunoglobulin E (IgE) antibodies, which can cause a variety of symptoms, including life-threatening anaphylaxis. A central step in this immune response to food antigens that differentiates tolerance from allergy is the initial priming of T cells by antigen-presenting cells (APCs), primarily different types of dendritic cells (DCs). DCs, along with monocyte and macrophage populations, dictate oral tolerance versus allergy by shaping the T cell and subsequent B cell antibody response. A growing body of literature has shed light on the conditions under which antigen presentation occurs and how different types of T cell responses are induced by different APCs. We will review APC subsets in the gut and discuss mechanisms of APC-induced oral tolerance versus allergy to food identified using mouse models and patient samples.