Stromal Cell Induction of Regulatory Dendritic Cells

Abstract

Dendritic cells (DCs) are specialized antigen presenting cells of bone marrow origin that can exist in tissues in either an immature or mature state. DCs have a myriad of roles in immunity and tolerance induction, but are perhaps best known for their role in the activation and differentiation of naïve T cells at the onset of an acquired immune response. Over the past decade, a body of literature has developed that suggests that DCs, as well as many other myeloid cell populations, are also capable of exerting “regulatory” effects on T cell responses. However, relatively little is known regarding the mechanisms by which such regulatory myeloid cells arise in vivo. In this mini-review, we first define the characteristics of “regulatory” DCs (rDCs) and then focus on the contribution of non-hematopoietic stromal cells to their generation within specific tissue microenvironments. We also highlight areas of research that warrant future attention, arguing for a focusing of efforts toward a better understanding of the features of stromal cell populations that enable the induction of rDCs. Finally, we discuss how an understanding of stromal cell-myeloid cell interactions may lead to new therapeutic strategies for cancer, autoimmunity, and infectious disease.

Stromal cell regulation of homeostatic and inflammatory lymphoid organogenesis

“…As well as maintaining peripheral tolerance via tissue‐specific antigen expression, in SLOs they have been shown to directly suppress T‐cell proliferation via nitric oxide production and regulate CD8 + T‐cell function via PD‐L1 expression during viral infection . In addition it appears that stromal cells of multiple organs are naturally predisposed to the generation of immunoregulatory myeloid cell populations . Therefore techniques could be developed to selectively activate or target stromal cells for the initiation of tolerogenic or regulatory responses, although much needs to be revealed regarding the differential mechanisms underlying inflammatory and tolerogenic stromal cell activation before this becomes a realistic option.…”

Capacity of Lung Stroma to Educate Dendritic Cells Inhibiting Mycobacteria-Specific T-Cell Response Depends upon Genetic Susceptibility to Tuberculosis

“…In earlier studies it was firmly established that DCreg release their suppressive potential by secreting a number of soluble factors capable to inhibit T cell responses, e.g., PGE 2, IL-10 and NO ( [15,17]; reviewed in [19]). To evaluate possible inhibitory activity of PGE 2 in our experiments, we developed DCreg on lung stroma in the presence (10µg/ml) or absence of the prostaglandin synthesis inhibitor indometacin and compared their capacity to inhibit T cell proliferation.…”

“…As emphasized in a recently published review [19], there are large gaps in our knowledge regarding the identity of regulatory DC. It is not clear whether regulatory DC are terminally differentiated cells or represent a transient functional state of a more general DC population triggered by the contact with stroma in an environment of organs.…”

“…More generally, data are lacking on possible role of DCreg during chronic bacterial infections, and the importance to gain relevant knowledge was recently emphasized [19]. Potential influence of the host genetic susceptibility to infection on parameters of DCreg induction/function was addressed to for the first time in Leishmania model [16].…”

The Effect of Traditional Chinese Formula Danchaiheji on the Differentiation of Regulatory Dendritic Cells

“…DCregs can be generated via multiple pathways, including immunosuppressive mediators such as conventional IS drug [ 21 , 22 ] and anti-inflammatory cytokines [ 23 ]; tissue microenvironment factors such as stromal, epithelial, and tumor cells [ 24 – 26 ]; and genetic manipulation of key molecules [ 27 ]. However, the method most suitable for generating DCregs for clinical application has not yet been defined [ 28 ].…”