Suppression of NK by Immuneregulatory Cells

Regulatory T cells (Treg) inhibition of NK functions was demonstrated in vitro and in vivo using anti-CD25 mAb against Tregs. In this model, CD25-depletion was also demonstrated to enhance NK activity in vitro [144, 145], suggesting that Tregs potentially inhibit NK cells. In mice with FoxP3 defect NK proliferation is enhanced [146], whereas adoptive Tregs transfer inhibit NK functions [147]. Similarly, human CD4+ CD25+ T cells were shown to impair NK cytotoxicity in vitro [148, 149]. Moreover, investigation of human gastrointestinal stromal tumor patients whom did not respond well to Gleevec demonstrated a higher Tregs numbers that were correlated with lower NK activity [150]. In agreement with these results, melanoma patients demonstrated increased NK functions if Tregs levels were low [151]. Tregs inhibition of NK activity was observed in a lung carcinoma model, where CD25-depletion enhanced the NK1.1+ cytotoxicity and resistance to tumor metastasis [152]. The rejection of allogeneic Bone-marrow transplanted cells was enhanced upon CD4+ CD25+ depletion in the recipient mice [153], and transplanted CD4+ CD25+ cells could protect bone-marrow progenitors form NK elimination. Experiments with thrombospondin-1 (TSP-1) deficient mice revealed its essential role in the inhibition of NK cells by Tregs [154]. Myeloid suppressor cells (CD11b+ Gr-1+) were shown to expand during tumor growth, and to suppress NK functions in vivo, through cell-cell contact that affect Stat5 and inhibit perforin synthesis [155].

Indirect effects complicate the situation even further, for example the TGFb production by iDCs is required for the optimal proliferation of Tregs [146]. Therefore, the elimination of iDCs by activated NK cells [139], would affect the physiological balance between activation and suppression by either omitting or allowing the initial signals. A comprehensive understanding of immune cells activities at the tumor site will enable the understanding of the complex relationships between these multiple cells types.

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