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In this issue of JEM, Taylor et al. describe PD-1 as a critical negative regulator of group 2 innate lymphoid cells (ILC-2s). PD-1 intrinsically controls proliferation and cytokine production of both mouse and human ILC-2s. PD-1 signaling inhibits STAT5 phosphorylation and the removal of this brake by knocking down PD-1 expression or by using anti–PD-1 blocking antibodies, translated in vivo into better clearance of helminth worm infection in mice.

A hallmark of chronic hepatitis B virus (HBV) infection is the functional impairment and depletion of antiviral T cells. In this issue of JEM, Pallett et al. identify a reservoir of functional HBV-specific T cells among liver-resident T cells.

Brief Definitive Report

Pallett et al. identify tissue-resident memory CD8 T cells compartmentalized in the healthy human liver that expand in controlled hepatotropic infection and can swiftly produce antiviral cytokines. This prototype may inform the development of liver-targeted T cell immunotherapy.

At the onset of adolescence, asthma becomes less prevalent in males than in females, suggesting a protective role of male sex hormones. Here, Laffont et al. show that androgens negatively control ILC2 development and ILC2-driven lung inflammation in male mice.

In Special Collection: Immunological Memory

Abdelsamed et al. demonstrate that the poised effector potential of human memory CD8 T cells is coupled to maintenance of effector-associated DNA methylation programs during in vitro and in vivo homeostatic proliferation.

IL-22 binding protein inhibits IL-22 signaling, which is important for intestinal homeostasis. Jinnohara et al. report that IL-22 binding protein is strongly expressed by Peyer’s patch dendritic cells and facilitates the M cell uptake of bacterial antigens into Peyer’s patches.

Pneumococci are major causes of bacterial meningitis. Iovino et al. show that pneumococci invade the brain and pass the blood–brain barrier by interacting with the endothelial receptors pIgR and PECAM-1 recognizing the pneumococcal adhesin RrgA and PspC on the bacterial surface.

Carrieri et al. identify a novel population of Miwi2-expressing undifferentiated spermatogonia. This population behave as transit-amplifying cells during homeostasis, but retain facultative stem cell activity and is critical for regenerative spermatogenesis.

Xu et al. show that Etv2 is required for hematopoietic stem and progenitor cell (HSPC) proliferation and expansion after bone marrow transplantation and hematopoietic injury. c-Kit functions downstream of Etv2 in mediating HSPC proliferation and expansion.

He et al. demonstrate that SMAC mimetic is efficient to target caspase-8–deficient colorectal cancer by induction of necroptosis. This study represents an attractive strategy for overcoming apoptosis resistance in colorectal cancer for the development of more effective personalized therapy.


Taylor et al. show that PD1 negatively regulates KLRG1+ ILC-2s by attenuating STAT5 activation. Blocking PD1 signaling significantly enhances the protective function of ILC-2s in helminthic infection.

In Special Collection: Lymphocytes and their Roles in Cancer

Integrin targeting for cancer has primarily focused on antagonizing integrin function, which has been clinically ineffective to date. In this study, Kwan et al. repurpose integrins as a beacon for recruiting immune effector functions to bolster current cancer immunotherapy approaches.

Drug tolerance brought about by reversible adaptive responses precedes the emergence of irreversible mutation-driven drug resistance and sustains tumor cells when at their most vulnerable. Young et al. delineate a signaling relay incorporating IL-1 and CXCR2 ligands emanating from melanoma-associated macrophages and fibroblasts, respectively, that confer tolerance to MAPK inhibitors.

Daley et al. show that NLRP3 signaling in macrophages drives their immune-suppressive phenotype in the pancreatic tumor microenvironment and potentiates tolerogenic T cell differentiation. Conversely, targeting NLRP3 protects against pancreatic oncogenesis and is associated with immunogenic reprograming within the tumor.

NLRP3 is an innate immune receptor that needs to be tightly regulated to prevent overshooting immune responses. Stutz et al. demonstrate that NLRP3 is phosphorylated as a safeguard against accidental activation, and that dephosphorylation involving PP2A activity is required for NLRP3 activation.

Neudecker et al. define a role for a microRNA, miR-223, in regulating the inflammatory tone of the intestine by constraining nlrp3 inflammasome activation in CCR2+ monocytes and attenuating excessive IL-1β–driven inflammation. Therapeutic nanoparticle delivery of miR-223 mimetics limits experimental colitis.

Pathological neovessels growing into the normally avascular photoreceptors cause vision loss in many eye diseases. Sun et al. find that a master inflammatory regulator, c-Fos, in photoreceptor controls retinal blood vessel growth into the photoreceptors through the inflammatory signal–induced STAT3/VEGFA pathway.

The innate sensor STING is critical for innate immune activation, but its role in adaptive immunity is unknown. By studying pathogenic mutations in STING found in patients, Cerboni et al. show that active STING inhibits proliferation in T lymphocytes.

Miao et al. report a checkpoint mediated by Egr2 and 3 that controls the transition between T cell clonal expansion and differentiation by regulating genes involved in proliferation and differentiation, which is essential for optimal immune responses with limited immunopathology.

Pelly et al. use novel mouse reporter systems to show that a proportion of Th2 cells develop from Foxp3-expressing cells in an IL-4–dependent manner, highlighting the potential to subvert T reg cell–mediated suppression in favor of type 2 immunity.

Djaoud et al. show that Epstein–Barr virus infection triggers two types of human innate immune response, one mediated by the combination of NK cells and γδ T cells and the other committed to a strong NK cell response with little involvement of γδ T cells.

In Special Collection: Tumor Metabolism

Xia et al. show that EGF receptor activation results in the binding of the RNF8 forkhead-associated domain to pyruvate kinase M2-phosphorylated histone H3-T11, leading to histone H3 polyubiquitylation and degradation and subsequent gene expression for tumor cell glycolysis and proliferation.

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