Figure 3.

Suppression of tumor immunity. Activated type I NKT cells have been shown to support immunosuppressive Tregs through IL-2 production, and are then suppressed by Tregs in a cell-contact-dependent manner. Treg cells can then suppress CD8⁺ and CD4⁺ T cells and NK cells (not shown). Sulfatide-reactive type II NKT cells suppress CD8⁺ T cells and inhibit proliferation of naïve, but not memory, CD4⁺ T cells. Type II NKT cells also suppress Type I, and while the exact mechanism in cancer settings remains unknown, the mechanism in a con-A-induced hepatitis model is believed to involve pDCs. Type II NKT cell production of IL-13 functions with TNF-α from other cells to increase production of TGF-β by a CD11b⁺Gr1⁺ population known as myeloid-derived suppressor cells (MDSCs). MDSCs not only directly support tumor growth with TGF-β production but also suppress other immune cells (e.g., CD8⁺ T and NK cells), feed into an autocrine loop to enhance development of additional tumor-associated MDSCs, and aid in expansion of Tregs. When tumor-induced inflammatory proteins like SAA-1 stimulate suppressive IL-10 producing neutrophils, and type I NKT cells are not activated to alter that reaction, increased levels of IL-10 can induce Treg cells and potentiate further tumor growth.