Plasmacytoid dendritic cells of the gut: relevance to immunity and pathology

Abstract

Plasmacytoid dendritic cells (pDCs) are bone marrow-derived immune cells with the ability to express copious amounts of type I and III interferon (IFN) and can differentiate into antigen-presenting dendritic cells as a result of stimulation by pathogen-derived nucleic acid. These powerful combined functionalities allow pDCs to bridge the innate and adaptive immune systems resulting in a concerted pathogen response. The contribution of pDCs to gastrointestinal immunity is only now being elucidated and is proving to be a critical component in systemic immunity. This review will explore the immunology of pDCs and will discuss their involvement in human disease and tolerance with an emphasis on those in the gastrointestinal lymphoid tissue.

Keywords: Autoimmunity; GALT;; Gut;; Interferon;; Tolerance;; pDC;.

Figure 1. Activation of endosomal TLR-7 and TLR-9 in pDCs

The activation of TLR-7 or TLR-9 leads to recruitment of the myeloid differentiation primary response protein 88 (MyD88) via its Toll/interleukin-1 (IL-1) receptor (TIR) domain. MyD88 recruits the interleukin-1 receptor-associated kinase 4 (IRAK)-4, which in turn engages IRAK1 or IRAK2. Formation of the resultant complex promotes a conformational change in the kinase domains of the IRAKs, leading to their autophosphorylation and subsequent activation. Activated IRAK kinase complexes phosphorylate the TNF receptor associated factor 6 (TRAF6), which promotes the polyubiquitination of the NF-kappa-B essential modulator (NEMO), as well as itself. Ubiquitinated NEMO then engages the nuclear factor kappa-B kinase subunit alpha and beta (IKKα and β) to form the IκB kinase complex. IκB then liberates NF-κB dimers, leading to their translocation into the nucleus promoding transcription of proinflammatory cytokines. TRAF6 can also activate the mitogen-activated protein kinases kinase (MAPKK), which in turn activates mitogen-activated protein kinases (MAPKs), leading to the upregulation of B7 costimulatory molecules (CD80, CD86). Conversely, TRAF6 can directly interact with IKKα, which phosphorylates IFN regulatory factor 7 (IRF-7), promoting its translocation into the nucleus, thus initiating transcription of type I IFN. Alternatively, MyD88 engagement of phosphatidylinositide 3-kinases (PI3K) followed by protein kinase B (PKB), mammalian target of rapamycin (mTOR), and the adapter protein raptor, activates IKKα and circumvents the IRAK complexes. Activation of TLRs in early endosomes favors expression of IFN whereas activation of TLRs in late endosomes favors expression of inflammatory cytokines.