Volume 20 Issue 9, September 2019

The NFIL3–ZEB2–ID2 transcription-factor regulatory circuit switches the E protein–dependent +41 kb Irf8 enhancer in DC progenitors to the BATF3-dependent +32 kb Irf8 enhancer in mature cDC1s. Deletion of the cryptic +41 kb Irf8 enhancer impedes cDC1 development.

The transcription factor TOX epigenetically reprograms CD8⁺ T cells to drive T cell exhaustion during chronic infection and cancer. Although they are necessary for T cell persistence, these changes contribute to diminished anti-tumor function in exhausted cells.

Therapeutic efficacy in inflammatory diseases is hampered by disease complexity. A monoclonal antibody that neutralizes IL-1R3, the common co-receptor of most inflammatory IL-1 cytokines, opens up new perspectives in effective disease management.

GPD2, the mitochondrial glycerol-3-phosphate dehydrogenase, contributes to the shift in core metabolism in macrophages activated during infection and during the transition to an alternatively activated phenotype during tissue repair.

High-grade glioblastoma demonstrates exceedingly poor patient survival rates. In their Review, Lim and colleagues describe the immunological mechanisms involved in the control of glioblastoma and the outlook for immunotherapy.

Godfrey and colleagues review the basic biology, development, role in disease and immunotherapeutic potential of MAIT cells.

NK cells recognize class I and stress-associated ligands. Altfeld and colleagues identify the NK cell receptor NKp44 as directly interacting with the class II HLA-DP in a partially peptide-dependent manner and with functional consequences for NK cell activity.

Multiple cytokines in the proinflammatory IL-1 family share the co-receptor IL-1R3. Dinarello and colleagues show that a fully humanized antibody to IL-1R3 can effectively control inflammation and disease mediated not only by IL-1 but also by IL-33 and IL-36.

Bhandoola and colleagues show that the transcription factor TCF-1 restrains the dendritic cell lineage potential in innate lymphoid cell progenitors.

The transcription factor IRF8 is essential for classical type 1 dendritic cell (cDC1) development. Murphy and colleagues investigate in detail the molecular control of cDC1 fate specification by systematically unpicking the IRF8 enhancer regions.

Classical type 1 dendritic cells (cDC1s) are essential for activation of antiviral and anticancer T cell responses. Murphy and colleagues describe a genetic circuit that involves the transcription factors Nfil3, Id2 and Zeb2. This circuit imposes a molecular switch that allows cDC1 specification and development.

Horng and colleagues show that mitochondrial glycerol-3-phosphate dehydrogenase, a component of the glycerol phosphate shuttle, modulates a shift from inflammation to immunosuppression in activated macrophages.

Aifantis and colleagues identify the E3 ubiquitin ligase SPOP as a negative regulator of ‘emergency hematopoiesis’ in bone marrow hematopoietic stem progenitor cells.

Loss of the transcription factor Foxp3 impairs T_reg cell development and immune homeostasis. Chatila and colleagues use a series of Foxp3 mutants to show that its disruption results in altered T_reg cell metabolism and loss of regulation, which are rescuable by metabolic manipulation.

T_reg cells obstruct effective anticancer responses. Lee and colleagues describe a T_reg cell biomarker signature that is strongly associated with enhanced suppression and progression of human breast cancer.

PD-1 blockade can enhance antitumor responses in a subset of cases. Khleif and colleagues demonstrate that PD-1 blockade in the context of suboptimal T cell activation engenders a state of non-responsiveness but not when there is strong stimulation by vaccination.

MAIT cells recognize the microbial metabolite 5-OP-RU and are selected on DP thymocytes expressing the MHC class Ib molecule MR1. Lantz and colleagues identify 5-OP-RU-specific thymocytes that are selected on thymic epithelial cells and differentiate into naive T cells.