Interaction between natural killer cells and regulatory T cells: perspectives for immunotherapy

Abstract

Regulatory T (Treg) cells and natural killer (NK) cells are key players in the immune system. The interaction between these two cell types has been reported to be beneficial in healthy conditions such as pregnancy. However, in the case of certain pathologies such as autoimmune diseases and cancer this interaction can become detrimental, as Treg cells have been described to suppress NK cells and in particular to impair NK cell effector functions. This review aims to discuss the recent information on the interaction between Treg cells and NK cells under healthy and pathologic conditions, to describe the specific conditions in which this interaction takes place, the effect of Treg cells on hematopoietic stem cell differentiation and the consequences of this interaction on the optimization of immunotherapeutic protocols.

Figure 1

Effect of Treg cells on NK cell function. Treg cells suppress NK cells through membrane bound TGF-β in allogeneic resting conditions (a) or when Treg cells are activated for example by APC, in both autologous and allogeneic settings (b). However, NK cells overcome this suppression in a cytokine milieu, such as IL-2 (c). Furthermore, antigen-specific iTregs enhance NK cell functions. This effect can be synergized with the addition of IL-2 (d). APC, antigen-presenting cells; IFN-γ, interferon-gamma; IL, interleukin; iTreg, induced Treg; NK, natural killer; TGF-β, transforming growth factor-beta; Treg, regulatory T.

Figure 2

Hypothesis of the effects of Treg cells on HSC and NK cell differentiation. TGF-β can promote the differentiation of myeloid progenitors rather than lymphoid progenitors. Furthermore, Treg cells may affect late stages of NK cell differentiation through TGF-β in addition to affecting NK cell IFN-γ, perforin and granzyme B production. T-bet and PU.1 expression could be affected by TGF-β signaling and hampered NK cell differentiation and functions. CLP, common lymphoid progenitor; HSC, hematopoietic stem cell; IFN-γ, interferon gamma; MLP, myeloid progenitor, NK, natural killer; NKP, NK progenitor, iNK, immature NK, mNK, mature NK; TGF-β, transforming growth factor-beta; Treg, regulatory T.