Adaptive control of NK cells

Credit: PIXTAL

Forkhead box P3 (FOXP3)⁺ regulatory T (T_Reg) cells maintain peripheral self-tolerance by suppressing the responsiveness of other immune cells, including natural killer (NK) cells. Three recent studies have discovered a mechanism by which T_Reg cells regulate NK cells.

In the first study by Gasteiger et al., the authors found that NK cell reactivity to strong activating signals, as well as their tolerance to self ligands, was not affected by the absence of T_Reg cells. However, NK cell-mediated targeting of MHC class I-deficient cells (which lack NK cell inhibitory receptors; also known as the 'missing-self response') was greatly enhanced in the absence of T_Reg cells. Interleukin-2 (IL-2) neutralization reversed this enhanced missing-self response, as did the depletion of CD4⁺ T cells, which readily produce IL-2 in T_Reg cell-deficient mice. These data suggest that T_Reg cells specifically suppress NK cell reactivity to missing-self targets by limiting the availability of CD4⁺ T cell-derived IL-2.

Of note, IL-2, which was shown to increase the adhesiveness of NK cells to missing-self targets, also enhanced NK cell adhesion to, and NK cell-mediated killing of, 'weak' targets — that is, cells that are normally inefficiently killed by NK cells.

T_Reg cells control the activity of NK cells by limiting their exposure to T cell-derived IL-2

In the second study by this group, the minor CD127⁺ NK cell splenic population was shown to increase in the absence of T_Reg cells. This expanded population comprised mainly immature NK cells that gave rise to mature CD11b⁺ NK cells following their transfer to lymphopenic hosts. CD127⁺ NK cells were the only NK cells that expressed CD25 (the high-affinity receptor for IL-2). The expression of CD25 by these cells was upregulated in response to the pro-inflammatory cytokine IL-12, levels of which are increased following T_Reg cell depletion. The expansion of the CD127⁺ NK cell population in the absence of T_Reg cells depended on the presence of CD4⁺ T cells and on IL-2, which suggests that T_Reg cells control the homeostasis of this immature NK cell population by restricting T cell-derived IL-2 availability. Interestingly, immature CD127⁺ NK cells also accumulated in tumour-bearing and chronically infected mice.

In a third study, Sitrin et al. showed that following acute T_Reg cell depletion in BDC2.5/NOD mice (a model of type 1 diabetes), pancreas-infiltrating NK cells were activated and had enhanced IL-2-induced gene expression. IL-2 neutralization in T_Reg cell-depleted BDC2.5/NOD mice reduced NK cell accumulation and their production of interferon-γ (IFNγ), which the group had previously shown to promote disease in this model. Correspondingly, supplementation of T_Reg cell-sufficient BDC2.5/NOD mice with IL-2 induced pancreatic NK cell proliferation and IFNγ production. The main source of IL-2 in this model was found to be CD4⁺ T cells in the pancreas.

Taken together, these studies suggest that T_Reg cells control the activity of NK cells by limiting their exposure to T cell-derived IL-2. These findings have important implications for the therapeutic manipulation of NK cells and for IL-2-based immunotherapies.