The thin line between conventional dendritic cells (cDCs) and group 3 innate lymphoid cells (ILC3s) in the gut

Abstract

Dendritic cells (DCs) express major histocompatibility complex class II (MHC-II) and are best known for proficiently presenting antigens to T cells, thereby eliciting specific adaptive T cell responses. Moreover, conventional DCs (cDCs) are specifically adept at handling intestinal antigens. Relatively recent discoveries and investigations have proven the existence of a new group of innate lymphocytes that reside in tissues like the intestine. They lack specific antigen receptors and can express MHC-II. These group 3 innate lymphoid cells (ILC3s) comprise a subset of heterogeneous innate lymphocytes that mirror the phenotype and functions of T-helper cells and act in the first line of defense. Considering that ILC3s are crucial for maintaining homeostasis of the intestinal mucosa and are found in niches alongside DCs, we herein describe the roles played by cDCs and ILC3s in the gut, highlighting the most recent studies. We discuss how these cells are alike and differ, constantly pointing out the thin, blurry line that separates cDCs and ILC3s.

Keywords: antigen presentation; colitis; microbiota.

Graphical Abstract

Fig. 1.

The hematopoietic origin of ILC and DC subsets. Immune cells originate from a hematopoietic stem cell in the bone marrow, which transitions through a series of developmental stages. In particular, cDCs and ILCs originate from the differentiation of distinct hematopoietic progenitors. Whereas most pDCs derive from a common lymphoid progenitor, all cDCs develop from the common DC progenitor, which emerges from the monocyte-dendritic cell progenitor—a process dependent on IRF8. In contrast, the ILC-restricted progenitor (common innate lymphoid progenitor) derives from the CLP, giving rise to two main lineages of ILCs, the killer ILC progenitor [natural killer progenitor (NKP)] and the helper-like progenitor (CHILP). Group 3 ILCs, as well as groups 1 and 2 ILCs, are then derived from the ILC progenitor (ILCP). However, CCR6⁺ ILC3s (LTi) are derived from a distinct progenitor called LTiP. Characteristic transcription factors found in ILC and cDC subsets are also shown. cNK, conventional natural killer; CMP, common myeloid progenitor; GMP, granulocyte-monocyte progenitor.

Fig. 2.

The spectrum of features that distinguish tolerogenic APCs and ILC3s. On the left (purple) is a tolerogenic APC that characteristically produces immunosuppressive cytokines like IL-10 and TGF-β, expresses the co-stimulatory molecules CD40 and CD86, the chemokine receptor CCR7 and the integrin CD11c and develops by signaling through the FLT3 receptor. On the right (gray) is an ILC3, which can produce lymphotoxin, IL-22, IL-17 and GM-CSF. It expresses CD90 and can express NKp46 (NCR1) and the chemokine receptor CCR6. Its development is dependent on signaling through the receptors CD127 and KIT. Transcriptionally, tolerogenic APCs depend on ZBTB46 and ILC3s depend on RORγt and AHR. In green are represented the molecules that have been reported to be expressed in both cell types, like MHC-II, integrin αvβ8 and the transcription factors ZBTB46 and RORγt.

Fig. 3.

Crosstalk between intestinal innate immune cells and the microbiota. Host-microbe interactions are two-way: intestinal epithelial cells especially can detect changes in the microbial environment and can respond functionally to adaptive immune cells, as well as cDCs and ILCs, which can react back to the commensal microbiota. In particular, ILCs are a heterogeneous population of cells that contribute to the maintenance of homeostasis and prevent the development of diseases. Together with cDCs, they are responsible for inducing tolerance to commensal microbiota and, during dysbiosis and/or infection, modulate the responses of other cells, such as phagocytes, and T and B cells.