Human NKT cells promote monocyte differentiation into suppressive myeloid antigen-presenting cells

Abstract

NKT cells have been shown to promote peripheral tolerance in a number of model systems, yet the processes by which they exert their regulatory effects remain poorly understood. Here, we show that soluble factors secreted by human NKT cells instruct human peripheral blood monocytes to differentiate into myeloid APCs that have suppressive properties. NKT instructed monocytes acquired a cell surface phenotype resembling myeloid DCs. However, whereas control DCs that were generated by culturing monocytes with recombinant GM-CSF and IL-4 had a proinflammatory phenotype characterized by the production of IL-12 with little IL-10, NKT-instructed APCs showed the opposite cytokine production profile of high IL-10 with little or no IL-12. The control DCs efficiently stimulated peripheral blood T cell IFN-gamma secretion and proliferation, whereas NKT-instructed APCs silenced these T cell responses. Exposure to NKT cell factors had a dominant effect on the functional properties of the DCs, since DCs differentiated by recombinant GM-CSF and IL-4 in the presence of NKT cell factors inhibited T cell responses. To confirm their noninflammatory effects, NKT-instructed APCs were tested in an in vivo assay that depends on the activation of antigen-specific human T cells. Control DCs promoted substantial tissue inflammation; however, despite a marked neutrophilic infiltrate, there was little edema in the presence of NKT-instructed APCs, suggesting the inflammatory cascade was held in check. These results point to a novel pathway initiated by NKT cells that can contribute to the regulation of human antigen-specific Th1 responses.

Peripheral blood mononuclear cells of patients with breast cancer can be reprogrammed to enhance anti-HER-2/neu reactivity and overcome myeloid-derived suppressor cells

“…Furthermore, the ability of NKT cells to direct myeloid lineage cellular differentiation is becoming apparent. Hedge and colleagues [48] have demonstrated the ability of NKT cells to induce the differentiation of monocytes into DCs as a result of secretion of GM-CSF and IL-13 and, similarly, others have reported on the ability of innate immune cells to induce the maturation of monocytes into DCs [49-51]. In animal models, NKT cells exhibit a regulatory function towards MDSCs through a CD1d-dependent mechanism [35].…”

Differential Requirement for P2X7R Function in IL-17 Dependent vs. IL-17 Independent Cellular Immune Responses

“…Footpads from SCID mice were harvested and submitted for routine histology and immunohistochemical (IHC) staining as described previously (22). …”

Human Vγ9/Vδ2 T cells: Innate adaptors of the immune system

“…While activated Vc9/Vd2 T cells can drive the differentiation of monocytes into inflammatory DCs [60,61], it is unclear whether iNKT cells can do the same. Instead, iNKT cells appear to promote the differentiation of monocytes into IL-10 secreting myeloid-derived suppressor cells (MDSCs) [165,166].…”

“…While activated Vc9/Vd2 T cells can drive the differentiation of monocytes into inflammatory DCs [60,61], it is unclear whether iNKT cells can do the same. Instead, iNKT cells appear to promote the differentiation of monocytes into IL-10 secreting myeloid-derived suppressor cells (MDSCs) [165,166].Similarly to Vc9/Vd2 T cells, iNKT cells can also provide help for B cell maturation and antibody production. In murine models, CD1d and iNKT cells are required for the generation of protective antibody responses against microbial pathogens [167][168][169].…”