ABSTRACT
Intestinal IL-17-producing cells, including Th17, γ/δ T, and innate lymphoid cells, are differentially distributed along the gastrointestinal tract. In this study, we show that the gut IL-17-producing γ/δ T (γ/δ T17) cells develop before birth and persist in the tissue as long-lived cells with minimal turnover. Most colon γ/δ T17 cells express, together with Vγ4 and CCR6, the scavenger receptor 2 and are mainly restricted to innate lymphoid follicles in the colon. Colon γ/δ T cells in mice that lack conventional dendritic cells 2 produced increased amounts of IL-17 with concomitant heightened epithelial antimicrobial response, such as the C-type lectins Reg3γ and Reg3ß. In the absence of γ/δ T cells or after IL-17 neutralization, this epithelial response was dramatically reduced, underlining the protective role of this unique subpopulation of innate γ/δ T17 cells in the colonic mucosa.
Subject(s)
Anti-Infective Agents/metabolism , Colon/immunology , Epithelial Cells/immunology , Intestinal Mucosa/immunology , Pancreatitis-Associated Proteins/metabolism , T-Lymphocytes/immunology , Animals , Cell Differentiation , Cells, Cultured , Fetal Development , Immunity, Innate , Interleukin-17/metabolism , Lymphocyte Activation , Mice , Mice, Inbred C57BL , Mice, Transgenic , Receptors, Antigen, T-Cell, gamma-delta/metabolism , Receptors, CCR6/metabolism , Receptors, Scavenger/metabolismABSTRACT
Circulating CCR2+ monocytes are crucial for maintaining the adult tissue-resident F4/80hiMHCIIhi macrophage pool in the intestinal lamina propria. Here we show that a subpopulation of CCR2-independent F4/80hiMHCIIlow macrophages, which are the most abundant F4/80hi cells in neonates, gradually decline in number in adulthood; these macrophages likely represent the fetal contribution to F4/80hi cells. In colon adenomas of ApcMin/+ mice, F4/80hiMHCIIlow macrophages are not only preserved, but become the dominant subpopulation among tumour-resident macrophages during tumour progression. Furthermore, these pro-tumoural F4/80hiMHCIIlow and F4/80hiMHCIIhi macrophages can self-renew in the tumour and maintain their numbers mostly independent from bone marrow contribution. Analyses of colon adenomas indicate that CSF1 may be a key facilitator of macrophage self-renewal. In summary, the tumour microenvironment creates an isolated niche for tissue-resident macrophages that favours macrophage survival and self-renewal.
Subject(s)
Adenoma/immunology , Cell Self Renewal , Colonic Neoplasms/immunology , Colonic Polyps/immunology , Macrophages/cytology , Stem Cell Niche , Tumor Microenvironment , Adenoma/genetics , Adenomatous Polyposis Coli Protein/genetics , Animals , Antigens, Differentiation , Cell Survival , Colonic Neoplasms/genetics , Colonic Polyps/genetics , Histocompatibility Antigens Class II , Macrophage Colony-Stimulating Factor , Mice , Mice, Knockout , Mice, Transgenic , Neoplasms, Experimental , Receptors, CCR2/geneticsABSTRACT
Dendritic cells (DCs) and macrophages (MÏs) share close developmental pathways and functional features, leading to blurring of the boundaries between these two cell lineages. However, a deeper understanding of DC and MÏ ontogeny and more refined phenotypic and functional characterizations have helped to delineate pre-DC-derived conventional DCs (cDCs), including cDC1s and cDC2s, from monocyte-derived MÏs. Here, we further refine DC/MÏ cell classification and report that classically defined cDC2s contain a discrete population of monocyte-derived migratory antigen-presenting cells with MÏ phenotype but functional DC features, including cross-presentation.