Mesenteric lymph node CD11b⁻ CD103⁺ PD‐L1^High dendritic cells highly induce regulatory T cells

Abstract

Dendritic cells (DCs) in mesenteric lymph nodes (MLNs) induce Foxp3 regulatory T cells to regulate immune responses to beneficial or non-harmful agents in the intestine, such as commensal bacteria and foods. Several studies in MLN DCs have revealed that the CD103 DC subset highly induces regulatory T cells, and another study has reported that MLN DCs from programmed death ligand 1 (PD-L1) -deficient mice could not induce regulatory T cells. Hence, the present study investigated the expression of these molecules on MLN CD11c cells. Four distinct subsets expressing CD103 and/or PD-L1 were identified, namely CD11b CD103 PD-L1 , CD11b CD103 PD-L1 , CD11b CD103 PD-L1 and CD11b CD103 PD-L1 . Among them, the CD11b CD103 PD-L1 DC subset highly induced Foxp3 T cells. This subset expressed Aldh1a2 and Itgb8 genes, which are involved in retinoic acid metabolism and transforming growth factor-β (TGF-β) activation, respectively. Exogenous TGF-β supplementation equalized the level of Foxp3 T-cell induction by the four subsets whereas retinoic acid did not, which suggests that high ability to activate TGF-β is determinant for the high Foxp3 T-cell induction by CD11b CD103 PD-L1 DC subset. Finally, this subset exhibited a migratory DC phenotype and could take up and present orally administered antigens. Collectively, the MLN CD11b CD103 PD-L1 DC subset probably takes up luminal antigens in the intestine, migrates to MLNs, and highly induces regulatory T cells through TGF-β activation.

Engineered Dendritic Cell-Directed Concurrent Activation of Multiple T cell Inhibitory Pathways Induces Robust Immune Tolerance

“…Of note, lentiviral transduction and LPS activation associated expression of secreted factors and cell surface molecules by ligand overexpressing DCs could contribute to modulation of T cell properties differently than that by APC subsets that naturally express elevated levels of these ligands. This is evident from our observation, in contrary to previous reports21,[49][50][51][52][53][54] , PD-L1 overexpressing engineered DCs do not induce an increase in Foxp3+ T cells, but these DCs suppress both Th1 and Th17 (IFNγ and IL17) responses. Nevertheless, the overall impact of engineered mono-and multi-ligand DCs on T cell function, as anticipated with enhanced engagement of T cell repressor receptors, is hyporesponsiveness/tolerance.…”

Aldehyde dehydrogenase in regulatory T‐cell development, immunity and cancer

“…Several recent manuscripts suggest a potentially important role for ALDH in immunity. This research has focused on the role of ALDH in Treg induction, function and resistance to cytotoxic therapy . The gastrointestinal tract, pulmonary tract and skin are the main organ systems that have been identified in which Treg cell activity is enhanced through ALDH (Fig.…”

“…In short, an immunological stimulus leads to, among other things, up‐regulation of ALDH in multiple cells . RA produced from ALDH then enhances Treg induction and function from naive CD4 + T cells . These antigen‐specific Treg cells then function to promote immune tolerance (Fig.…”

“…Much evidence for the role of ALDH in Treg induction and function comes from the study of the gastrointestinal tract . The intestinal immune system is exposed to a myriad of beneficial and non‐harmful antigens derived from ingested substances and organisms, such as foods and commensal bacteria .…”

Inhibins regulate peripheral regulatory T cell induction through modulation of dendritic cell function

“…These CD103 + DC subpopulations have been reported to play a key role in tolerance induction in the gut, as they produce high levels of RA and TGFb, which are key mediators of FoxP3 induction in the intestinal microenvironment [41,42]. In fact, it has been previously shown that CD103 + CD11b À PD-L1 hi DC are high inducers of pTregs [43], in agreement with the reported effect of PD-L1 during Treg conversion from na€ ıve T cells by immature DCs in vitro [44].…”