Transcription factor KLF2 regulates homeostatic NK cell proliferation and survival

Abstract

Natural killer (NK) cells are innate lymphocytes that recognize and lyse virally infected or transformed cells. This latter property is being pursued in clinics to treat leukemia with the hope that further breakthroughs in NK cell biology can extend treatments to other cancers. At issue is the ability to expand transferred NK cells and prolong their functionality within the context of a tumor. In terms of NK cell expansion and survival, we now report that Kruppel-like factor 2 (KLF2) is a key transcription factor that underpins both of these events. Excision of Klf2 using gene-targeted mouse models promotes spontaneous proliferation of immature NK cells in peripheral tissues, a phenotype that is replicated under ex vivo conditions. Moreover, KLF2 imprints a homeostatic migration pattern on mature NK cells that allows these cells to access IL-15-rich microenvironments. KLF2 accomplishes this feat within the mature NK cell lineage via regulation of a subset of homing receptors that respond to homeostatic ligands while leaving constitutively expressed receptors that recognize inflammatory cytokines unperturbed. Under steady-state conditions, KLF2-deficient NK cells alter their expression of homeostatic homing receptors and subsequently undergo apoptosis due to IL-15 starvation. This novel mechanism has implications regarding NK cell contraction following the termination of immune responses including the possibility that retention of an IL-15 transpresenting support system is key to extending NK cell activity in a tumor environment.NK cell | KLF2 | NK cell proliferation | NK cell homeostasis | IL-15

The biology of natural killer cells during sepsis

“…Natural killer cells are bone‐marrow‐derived large granular lymphocytes possessing a ‘natural’ ability to kill tumours without prior priming . Most recently, NK cells have been classified among a cohort of lymphocytes termed innate lymphoid cells .…”

“…Natural killer cells are bone-marrow-derived large granular lymphocytes possessing a 'natural' ability to kill tumours without prior priming. 54,55 Most recently, NK cells have been classified among a cohort of lymphocytes termed innate lymphoid cells. 56 Although NK cells and other innate lymphoid cells share lineage origin with T and B lymphocytes of the adaptive immune system, NK cells lack the expression of germ-line rearranged immunoglobulin and T-cell receptor genes.…”

Deconstructing deployment of the innate immune lymphocyte army for barrier homeostasis and protection

“…These cells express the IL‐2Rβ chain (CD122), Sca‐1, IL‐7Rα, and ID2 but lacked markers typically expressed on fully differentiated mature NK cells such as NK1.1, NKp46, and CD49b . In the bone marrow, this progenitor further committed into NK progenitor (NKP) and subsequently into immature and mature NK cells under the influence of a core transcription program including but not restricted to Id2 , Gata3 , Nfil3 , Klf2 , Eomes , Tbx21 , Tcf7 , Tox, and Ets‐1 (Figure ) . Interestingly, NFIL3 expression is essential for the development of all ILC subsets but appears to be only required early and transiently to implement the ILC program as Nfil3 deletion in ID2 + mature NK cells does not affect NK cell survival or function …”

“…Critical extracellular signals influencing ILC functions and mediating ILC plasticity are depicted. Networks were designed based on Ch IP data or reporter assays (thick lines) together with gene deletion or overexpression systems (regular lines) . Nonexpressed genes are depicted in gray.…”

Transcriptional regulatory networks that promote and restrict identities and functions of intestinal innate lymphoid cells

“…Beyond these lineage-defining TFs, the ILC networks accurately predicted several other TFs with known functions in various ILC lineages. These include TCF-1 (Tcf7) in CCR6 + ILC3 (Mielke et al, 2013); LEF1 (Held et al, 2003) and BLIMP-1 (Prdm1) (Kallies et al, 2011;Smith et al, 2010) in NK; KLF2 in NK and ILC1 (Rabacal et al, 2016); and PPARg in ILC2 (highlighted in bold, Figure 3A). Importantly, the majority of the 125 TFs are novel predictions, highlighting the utility of our network approach to markedly expand TF predictions beyond what is possible by standard motif enrichment analysis.…”