Natural Killer (NK) cells are innate lymphocytes that exhibit many features of adaptive immunity including clonal proliferation and long-lived memory. Here we demonstrate that the BTB-ZF transcription factor Zbtb32 (also known as ROG, FAZF, TZFP, and PLZP) is essential for the proliferative burst and protective capacity of virus-specific NK cells. Signals from proinflammatory cytokines are both necessary and sufficient to induce high Zbtb32 expression in NK cells. Mechanistically, we show that Zbtb32 facilitates NK cell proliferation during infection by antagonizing the anti-proliferative factor Blimp-1 (Prdm1). Taken together, our data support a model in which Zbtb32 acts as a cellular “hub” through which pro-inflammatory signals instruct a “proliferation-permissive” state in NK cells, thereby allowing their prolific expansion in response to viral infection.

Inflammatory cytokines drive NK cell expansion in the absence of the transcription factor Nfil3, and Nfil3 is dispensable for the maintenance and function of mature NK cells.

Natural killer (NK) cells function in the recognition and destruction of host cells infected with pathogens. Many regulatory mechanisms govern the potent responses of NK cells, both at the cellular and molecular level. Ablation of microRNA (miRNA) processing enzymes demonstrated that miRNAs play critical roles in NK cell differentiation and function; however, the role of individual miRNAs requires further investigation. Using mice containing a targeted deletion of microRNA-155 (miR-155), we observed defects in NK cell maintenance and maturation at steady state, as well as in homeostatic proliferation in lymphopenic mice. In addition, we discovered that miR-155 is up-regulated in activated NK cells during mouse cytomegalovirus (MCMV) infection in response to signals from the proinflammatory cytokines IL-12 and IL-18 and through signal transducer and activator of transcription 4 (STAT4) signaling. Although miR-155 was found to be dispensable for cytotoxicity and cytokine production when triggered through activating receptors, NK cells lacking miR-155 exhibited severely impaired effector and memory cell numbers in both lymphoid and nonlymphoid tissues after MCMV infection. We demonstrate that miR-155 differentially targets Noxa and suppressor of cytokine signaling 1 (SOCS1) in NK cells at distinct stages of homeostasis and activation. NK cells constitutively expressing Noxa and SOCS1 exhibit profound defects in expansion during the response to MCMV infection, suggesting that their regulation by miR-155 promotes antiviral immunity.

Successful immunity depends upon the activity of multiple cell types. Therefore, commitment of pluripotent precursor cells to specific lineages, such as T or B cells, is obviously fundamental. However, it is also becoming clear that continued differentiation and specialization of lymphoid cells is equally important for immune system integrity. Several members of the BTB-ZF family have emerged as critical factors that control development of specific lineages and also of specific effector subsets within these lineages. For example, BTB-ZF genes have been shown to control T cell versus B cell commitment and CD4 versus CD8 lineage commitment. Others, such as PLZF for NKT cells and Bcl6 for T follicular helpers cells, are necessary for the acquisition of effector functions. Here we summarize current findings concerning the BTB-ZF family members with reported role in the immune system.

Type 2 cytokine responses promote parasitic immunity and initiate tissue repair but, can also result in immunopathologies when not properly restricted. Basophilia is recognized as a common feature of type 2 inflammation, however, the roles basophils play in regulating these responses remain unknown. Here, we demonstrate that helminth-induced ILC2 responses are exaggerated in the absence of basophils, resulting in increased inflammation and diminished lung function. Additionally, we show that ILC2s from basophil-depleted mice express reduced amounts of the receptor for the neuropeptide, neuromedin B (NMB). Critically, NMB stimulation inhibited ILC2 responses from control but not basophil-depleted mice, and basophils were sufficient to directly enhance NMB receptor (NMBR) expression on ILC2s. These studies suggest that basophils prime ILC2s to respond to neuron-derived signals necessary to maintain tissue integrity. Further, these data provide mechanistic insight into the functions of basophils and identify NMB as a potent inhibitor of type 2 inflammation.