RESUMEN
CD103+CD11b+ dendritic cells (DCs) are unique to the intestine, but the factors governing their differentiation are unclear. Here we show that transforming growth factor receptor 1 (TGFßR1) has an indispensable, cell intrinsic role in the development of these cells. Deletion of Tgfbr1 results in markedly fewer intestinal CD103+CD11b+ DCs and a reciprocal increase in the CD103-CD11b+ dendritic cell subset. Transcriptional profiling identifies markers that define the CD103+CD11b+ DC lineage, including CD101, TREM1 and Siglec-F, and shows that the absence of CD103+CD11b+ DCs in CD11c-Cre.Tgfbr1 fl/fl mice reflects defective differentiation from CD103-CD11b+ intermediaries, rather than an isolated loss of CD103 expression. The defect in CD103+CD11b+ DCs is accompanied by reduced generation of antigen-specific, inducible FoxP3+ regulatory T cells in vitro and in vivo, and by reduced numbers of endogenous Th17 cells in the intestinal mucosa. Thus, TGFßR1-mediated signalling may explain the tissue-specific development of these unique DCs.Developmental cues for the different dendritic cell (DC) subsets in the intestine are yet to be defined. Here the authors show that TGFßR1 signalling is needed for development of CD103+CD11b+ intestinal DCs from CD103-CD11b+ cells and that they contribute to the generation of Th17 and regulatory T cells.
Asunto(s)
Diferenciación Celular/genética , Células Dendríticas/inmunología , Mucosa Intestinal/inmunología , Proteínas Serina-Treonina Quinasas/genética , Receptores de Factores de Crecimiento Transformadores beta/genética , Linfocitos T Reguladores/inmunología , Células Th17/inmunología , Animales , Antígenos CD/inmunología , Antígeno CD11b/inmunología , Linaje de la Célula , Colitis/inmunología , Células Dendríticas/citología , Inmunidad Mucosa , Cadenas alfa de Integrinas/inmunología , Mucosa Intestinal/citología , Intestinos/citología , Intestinos/inmunología , Linfopoyesis/genética , Ratones , Ratones Noqueados , Receptor Tipo I de Factor de Crecimiento Transformador beta , Linfocitos T Reguladores/citología , Células Th17/citologíaRESUMEN
The intestinal lamina propria (LP) contains a diverse array of mononuclear phagocyte (MNP) subsets, including conventional dendritic cells (cDC), monocytes and tissue-resident macrophages (mφ) that collectively play an essential role in mucosal homeostasis, infection and inflammation. In the current review we discuss the function of intestinal cDC and monocyte-derived MNP, highlighting how these subsets play several non-redundant roles in the regulation of intestinal immune responses. While much remains to be learnt, recent findings also underline how the various populations of MNP adapt to deal with the challenges specific to their environment. Understanding these processes should help target individual subsets for 'fine tuning' immunological responses within the intestine, a process that may be of relevance both for the treatment of inflammatory bowel disease (IBD) and for optimized vaccine design.
Asunto(s)
Inmunoterapia/métodos , Enfermedades Inflamatorias del Intestino/inmunología , Mucosa Intestinal/inmunología , Leucocitos Mononucleares/inmunología , Fagocitos/inmunología , Vacunas/inmunología , Animales , Humanos , Inmunidad Mucosa , Inmunomodulación , Enfermedades Inflamatorias del Intestino/terapiaRESUMEN
Macrophages (mφ) are essential for intestinal homeostasis and the pathology of inflammatory bowel disease (IBD), but it is unclear whether discrete mφ populations carry out these distinct functions or if resident mφ change during inflammation. We show here that most resident mφ in resting mouse colon express very high levels of CX3CR1, are avidly phagocytic and MHCII(hi), but are resistant to Toll-like receptor (TLR) stimulation, produce interleukin 10 constitutively, and express CD163 and CD206. A smaller population of CX3CR1(int) cells is present in resting colon and it expands during experimental colitis. Ly6C(hi)CCR2(+) monocytes can give rise to all mφ subsets in both healthy and inflamed colon and we show that the CX3CR1(int) pool represents a continuum in which newly arrived, recently divided monocytes develop into resident CX3CR1(hi) mφ. This process is arrested during experimental colitis, resulting in the accumulation of TLR-responsive pro-inflammatory mφ. Phenotypic analysis of human intestinal mφ indicates that analogous processes occur in the normal and Crohn's disease ileum. These studies show for the first time that resident and inflammatory mφ in the intestine represent alternative differentiation outcomes of the same precursor and targeting these events could offer routes for therapeutic intervention in IBD.