GATA-3 Promotes Maturation, IFN-γ Production, and Liver-Specific Homing of NK Cells

Abstract

The GATA-3 transcription factor has a determinant role in T cell specification and is an essential mediator of T helper 2-type polarized immune responses. While both committed NK precursors and mature NK cells express GATA-3, a role of this transcription factor in murine NK cell differentiation is not known. We found that NK cells, in contrast to T cells, can be generated in the absence of GATA-3. However, while GATA-3 antagonizes IFN-gamma production in differentiating T cells, GATA-3-deficient NK cells paradoxically produced less IFN-gamma compared to control NK cells and failed to provide early protection in vivo against infection with Listeria monocytogenes. Surprisingly, GATA-3 was essential for NK cell homing to the liver. Our results suggest that GATA-3 promotes NK cell maturation and acts in this lineage to specify distinct effector phenotypes.

Continuous CD27 triggering in vivo strongly reduces NK cell numbers

“…This hypothesis is supported by the findings that only CD11b low CD43 À NK cells are present in mice deficient for several different transcription factors, such as GATA-3, IRF2 or T-bet, and in mice bearing constitutively active NFkB. In all these models, the CD11b low CD43 À NK cells exhibit normal cytotoxic capacities [38][39][40][41].…”

“…Hence, we evidenced opposite effects of CD70 triggering on the major NK cell effector functions. Different outcomes of those NK cell effector functions upon the same triggering have been described before, for example in the GATA-3 deficient mouse model [38]. On the other hand, as several hours are required for ifn-g transcription and translation, the NK cells were incubated for 6 h in the IFN-g assay, during which the higher apoptosis in the mNK cell population of CD70-Tg mice can have an important impact.…”

“…This hypothesis is supported by the findings that only CD11b low CD43 À NK cells are present in mice deficient for several different transcription factors, such as GATA-3, IRF2 or T-bet, and in mice bearing constitutively active NFkB. In all these models, the CD11b low CD43 À NK cells exhibit normal cytotoxic capacities [38][39][40][41].In our study, we found that splenic NK cells from CD70-Tg mice, whether stimulated through the IL-12/IL-18 receptor or through the NK1.1 receptor, produced less IFN-g compared with WT NK cells, whereas in liver no differences were demonstrated. Regarding cytotoxicity, both liver and splenic NK cells from CD70-Tg mice showed increased activity.…”

Deletion of PI3K-p85α gene impairs lineage commitment, terminal maturation, cytokine generation and cytotoxicity of NK cells

“…Both PLCg2 and PI3K are known to regulate a number of transcription factors. However, their role in regulating transcription factors such as T-bet, 52 GATA-3, 53 IFNregulatory factor-1, 54 IRF-2, 55 ID2, 56 Ets-1, 57 MEF 58 and PU-1 59 that are involved in NK cell development and maturation has yet to be elucidated. Indeed, earlier studies from Di Santo laboratory have shown that lack of GATA-3 reduces the levels of Ly49A, Ly49C/I and Ly49D NK subsets, whereas Ly49G2 and NKG2A/CD94 were unaffected.…”

“…Indeed, earlier studies from Di Santo laboratory have shown that lack of GATA-3 reduces the levels of Ly49A, Ly49C/I and Ly49D NK subsets, whereas Ly49G2 and NKG2A/CD94 were unaffected. 53 Thus, a lack of transcription factors such as GATA-3 could partially explain the reduction in Ly49 subsets in p85a À/À mice.…”