NKT cells direct monocytes into a DC differentiation pathway

Abstract

Monocytes can differentiate into macrophages or dendritic cells (DCs). The processes that promote their differentiation along one pathway rather than the other remain unknown. NKT cells are regulatory T cells that respond functionally to self and foreign antigens presented by CD1d molecules. Hence, in addition to contributing to antimicrobial responses, they may carry out autoreactively activated functions when there is no infectious challenge. However, the immunological consequences of NKT cell autoreactivity remain poorly understood. We show here that human NKT cells direct monocytes to differentiate into immature DCs. The ability to induce monocyte differentiation was CD1d-dependent and appeared specific to NKT cells. Addition of exogenous antigens or costimulation from IL-2 was not required but could enhance the effect. DC differentiation was a result of NKT cell secretion of GM-CSF and IL-13, cytokines that were produced by the NKT cells upon autoreactive activation by monocytes. NKT cells within PBMC samples produced GM-CSF and IL-13 upon exposure to autologous monocytes directly ex vivo, providing evidence that such NKT cell-autoreactive responses can occur in vivo. These results show that when NKT cells are activated by autologous monocytes, they are capable of providing factors that specifically direct monocyte differentiation into immature DCs. Thus, autoreactively activated NKT cells may contribute to the maintenance of the immature DC population, and microbial infection or inflammatory conditions that activate NKT cells further could stimulate them to promote an increased rate of DC differentiation.

Natural killer T-cell autoreactivity leads to a specialized activation state

“…We have recently shown that GM-CSF and IL-13 secretion by autoreactive NKT cells induces human monocytes to differentiate into immature DCs. 36 Hence, we speculate that the particular pattern of cytokine production resulting from NKT-cell autoreactive activation, comprising mainly GM-CSF and IL-13, may serve to constitutively promote monocyte differentiation into DCs. The identities of the auto-antigens recognized by human NKT cells remain unknown; thus, their TCR affinity is not clear.…”

“…34 DCs were prepared by short-term culture of fresh human peripheral blood monocytes with granulocyte macrophage colony-stimulating factor (GM-CSF) and IL-4 as described. 36 CD1d transfectants were generated from the 3023 human lymphoblastoid cell line as described. 37 Studies were approved by the University of Wisconsin Minimal Risk Institutional Review Board, and written informed consent was obtained from all blood donors in accordance with the Declaration of Helsinki.…”

TH1, TH2, and TH17 cells instruct monocytes to differentiate into specialized dendritic cell subsets

“…Previous studies have shown that NK, CD8 ϩ and NK T cells can also initiate DC differentiation. 31,45,46 Similar to T H cells, NK cells colocalize with monocytes in inflamed tissue and direct DC differentiation in a GM-CSF and cell contact dependent manner. 46 Comparison of the relative contributions of each of these cell types to inflammatory responses merits further investigation.…”

Immunosuppressive Myeloid-Derived Suppressor Cells Can Be Converted into Immunogenic APCs with the Help of Activated NKT Cells: An Alternative Cell-Based Antitumor Vaccine

“…Recently, it was reported that human-activated NKT cells direct monocytes to differentiate into immature DCs (31) and that cytokines produced by the NKT cells, including IL-13 and GM-CSF, could induce differentiation in monocytes. In the current study, we found that the levels of CD11c and CD86 on MDSCs were increased by activated NKT cell-mediated stimulation in naive mice.…”