Top Reads

Receptor for activated C kinase 1 (RACK1) is an adaptor protein that can link viral proteins to protein kinase C, as well as other pathways. In this Top Read, Qin et al. (p. 1411) observed that RACK1-deficient macrophages develop normally and are less susceptible to influenza infection. RACK1-deficient macrophages expressed more type I IFNs in response to DNA or RNA virus infection. Further analysis revealed that viral infection induced phosphorylation of RACK1 at Thr⁵⁰, which enhanced interactions with IRF3/7, and prevented subsequent type I IFN expression. These findings better define a role for myeloid RACK1 in viral infection and its effects on type I IFN expression.

Dendritic cells (DCs) are critical players in maintaining immune tolerance and limiting inflammation, but the DC-intrinsic regulators of inflammation are not well understood. In this Top Read, Manoharan et al. (p. 1428) characterized a role for the T cell factor/lymphoid enhancer–binding factor (TCF/LEF) family member, TCF4, in DCs as a regulator of inflammatory responses. Previous studies have shown that TCF4 is highly expressed in DCs, and in this study the authors observed that induction of experimental autoimmune encephalitis (EAE) was associated with increased TCF4 expression in splenic and CNS-infiltrating DCs. Selective deletion of TCF4 in DCs (TCF4^ΔDC) did not alter development or differentiation, but exacerbated EAE symptoms and enhanced infiltration of Th1 and Th17 cells into the CNS. TCF4^ΔDC had elevated p38 MAPK signaling and greater proinflammatory cytokine expression, but blockade of p38 MAPK decreased EAE onset and severity. These data identify TCF4 in DCs as a regulator of inflammation that may be explored for therapeutic interventions.

Viral infections can induce inflammatory cytokine exp-ression, and a wide range of host proteins are involved in engaging with viral proteins to trigger these responses. In this Top Read, Burns and Kerppola (p. 1437) identified Kelch-like ECH associated protein 1 (Keap1) as a key mediator of cytokine induction during Sendai virus (SeV) infection. Previous studies have shown that Keap1 deletion in different immune cells leads to disparate outcomes in cytokine expression, which may depend on interactions with nuclear receptor subfamily 2 group f member 2 (Nrf2). In this study, the authors observed that SeV infection in mouse embryo fibroblasts induced Keap1 binding to cytokine genes, repressing their expression. Transcriptional repression occurred upon recruitment of NF-κB p50 and G9a-GLP lysine methyltransferase to chromatin and required the presence of Keap1 but not Nrf2. Keap1 formed complexes with NF-κB p50 and NF-κB p65 in living cells, which may facilitate chromatin binding. G9a-GLP inhibitors reversed transcriptional repression by Keap1, but also promoted Keap1 and NF-κB recruitment to cytokine genes. These data suggest a potential feedback circuit formed by Keap1, NF-κB, and G9a-GLP in regulating virus-induced cytokine expression.

Interleukin 9–producing Th (Th9) cells can differentiate in the presence of IL-4 and TGF-β. This subset responds to parasitic infection or tumors but is also associated with detrimental allergic responses and colitis. In this Top Read, Canaria et al. (p. 1265) observed STAT5-mediated repression of Th17-associated genes in human Th9 cells obtained from house dust mite–allergic individuals. In a murine model, blockade of IL-2/STAT5 signaling led to STAT3-independent expression of Rorγt and IL-7 production by Th9. In contrast, STAT3-deficient IL-2–deprived Th9 cells did not produce IL-17, but ectopic expression of the transcription factors Rorγt and BATF restored IL-17 production. Together, these data indicate a role for IL-2/STAT5 signaling in the polarization of Th9 into Th17-like cells and suggests that STAT3 contributes to their longer-term survival.

High densities of macrophages within tissues can lead to the resolution of inflammatory responses, and like bacteria, quorum-sensing mechanisms can be used by macrophages to sense the density of these cells and regulate their function. In this Top Read, Sharma et al. (p. 1250) observed upregulation of programmed cell death 4 (PDCD4) in high-density macrophages, and conditioned medium from these cells was sufficient to induce PDCD4 expression. Secreted gelsolin (GSN) was identified as the macrophage quorum-sensing autoinducer. LPS treatment induced microRNA-21 (miR-21) expression, which downregulated GSN and PDCD4 expression, reversing the anti-inflammatory phenotype of high-density macrophages. These findings indicate that GSN and PDCD4 are critical mediators of macrophage quorum sensing and can modulate inflammatory states.

Neuropilin-1 (Nrp-1) is known as a marker of CD4⁺Foxp3⁺ regulatory T cells (Tregs) but has also been detected on small subsets of naive and activated conventional CD4⁺ T cells. In this Top Read, Abberger et al. (p. 1288) examined the role of Nrp-1 on non-Treg CD4⁺ T cells. The authors observed that in vitro stimulation induced Nrp-1 expression on a subset of CD4⁺Foxp3⁻ T cells (iNrp-1⁺CD4⁺Foxp3⁻ T cells) that displayed a highly activated phenotype with elevated CD25 and CD44 expression and increased inflammatory cytokine production. In contrast, Nrp-1⁺CD4⁺Foxp3⁻ naive T cells (nNrp-1⁺CD4⁺Foxp3⁻ T cells) were dysfunctional and displayed defects in proliferation and activation upon in vitro stimulation, including elevated expression of PD-1 and CTLA-4. In a T cell transfer model of diabetes, transferred Ag-specific iNrp-1⁺CD4⁺ conventional T cells enhanced diabetes development, whereas transferred Ag-specific nNrp-1⁺CD4⁺ conventional T cells did not. These findings suggest that Nrp-1 expression is associated with the activation status of different functional subsets of non-Treg CD4⁺ T cells.