Abstract
Graft versus Host Disease (GvHD) remains one of the main complications after hematopoietic stem cell transplantation (HSCT). Due to their ability to suppress effector cells, regulatory T cells (Tregs) have been proposed as a cellular therapy to prevent GvHD, however they also inhibit the functions of natural killer (NK) cells, key effectors of the Graft versus Leukemia effect. In this study, we have explored whether a Tregs therapy will also impact on NK cell differentiation. Using an in vitro model of hematopoietic stem cell (HSC) differentiation into NK cells, we found that activated Tregs led to a 90% reduction in NK cell numbers when added at the time of commitment to the NK cell lineage. This effect was contact dependent and was reversible upon Tregs depletion. The few NK cells that developed in these cultures were mature and exhibited normal functions. Furthermore, adoptive transfer of activated Tregs in rag-/- γc-/- mice abrogated HSC differentiation into NK cells thus confirming our in vitro findings. Collectively, these results demonstrate for the first time that activated Tregs can inhibit NK cell differentiation from HSC under specific conditions.
Highlights
CD4+CD25highFoxp3high regulatory T cells (Tregs) are involved in the maintenance of self-tolerance and immune homeostasis[1]
To evaluate the effects of Tregs on natural killer (NK) cell differentiation, an established in vitro model of differentiation of cord blood (CB) hematopoietic stem cell (HSC) into NK cells was used[30]. This model is ideal to analyze the effect of Tregs on NK cell differentiation as HSC only differentiate into NK cells under the conditions used[31]
Whilst resting Tregs did not affect HSC differentiation (Fig. 1A and Figure S2 for representative FACS plots), a significant reduction in NK cell numbers were observed when activated Tregs where added to HSC at day 9 but not at another time points (Fig. 1B and Figure S2), with 90% reduction in NK cell numbers observed
Summary
CD4+CD25highFoxp3high regulatory T cells (Tregs) are involved in the maintenance of self-tolerance and immune homeostasis[1]. Studies in humans and mice demonstrated that Tregs inhibit NK cell functions via membrane bound TGF-β such as cytotoxicity and cytokine production[3,5,15,16,17,18], decrease the expression of key activating receptors[5,15], affect their proliferation[19], and that Tregs depletion in mice leads to increased NK cell numbers[5,20,21]. TGF-β impacts hematopoietic stem cell (HSC) functions by skewing their differentiation towards the myeloid over the lymphoid lineage[28]. Given that Tregs can control mature and immature NK cell responses, partly via TGF-β , and that TGF-β can affect HSC functions, one could expect that Tregs could affect NK cell differentiation from HSC. Reported cell counts were calculated from total cell numbers and cell ratios were determined by flow cytometry. ***P ≤ 0.005
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