Transcription factor KLF2 regulates homeostatic NK cell proliferation and survival.
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.
Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN 37232;
Whitney
W
Rabacal
Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN 37232;
Sudheer K
SK
Pabbisetty
Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN 37232;
Kristen L
KL
Hoek
Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN 37232;
Delphine
D
Cendron
Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232.
Yin
Y
Guo
Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN 37232;
Damian
D
Maseda
Department of Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; eric.sebzda@vanderbilt.edu.
Eric
E
Sebzda
D000818:Animals; D049109:Cell Proliferation / Q000502:physiology*; D002470:Cell Survival / Q000502:physiology*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D019409:Interleukin-15 / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000166:cytology* / Q000502:physiology*; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL
D019409:Interleukin-15; C498314:Klf2 protein, mouse; D051741:Kruppel-Like Transcription Factors
IL-15; KLF2; NK cell; NK cell homeostasis; NK cell proliferation