Volume 17 Issue 3, March 2016

SHARPIN acts independently of the ubiquitin-assembly complex LUBAC to attenuate proximal signaling downstream of TCRs by inhibiting the interaction of Zap70 with the TCRζ chain through Lys63 (K63)-linked polyubiquitination. SHARPIN deficiency enhanced TCR signaling and impaired the development and function of T_reg cells.

The NLRP3 inflammasome has broad biomedical relevance, but its activation mechanisms are incompletely understood. NEK7, a kinase that regulates microtubules during mitosis, is identified as a critical and selective upstream regulator of NLRP3 inflammasome activation.

An important new function for the phosphatase PTEN in regulating interferon responses to viral infection has been delineated. This finding could help explain the remarkable cancer selectivity of many oncolytic viruses.

The production of interleukin 12 (IL-12) and IL-23 in dendritic cells is strictly regulated via epigenetic silencing. This transcriptional repression is overcome with the help of the deubiquitinase Trabid and has functional implications in a mouse model of multiple sclerosis.

Inflammation is one of the hallmarks of cancer. Ben-Neriah and colleagues review the inflammatory networks underlying colorectal cancer.

PTEN functions as a tumor suppressor. Guo and colleagues now find PTEN also serves a critical role in antiviral innate immunity by inducing the production of type I interferon.

NEK7 is a serine-threonine kinase linked to mitosis. Beutler and colleagues show that NEK7 is required for assembly of the NLRP3 inflammasome and restricts NLRP3 activation to interphase of the cell cycle.

Sun and colleagues show that the deubiquitinase Trabid mediates the TLR-induced deubiqutination and stabilization of the histone demethylase Jmjd2d at the Il12 and Il23 promoters in dendritic cells.

The precise lineage relationship between innate lymphoid cells and lymphoid tissue–inducer cells is poorly understood. Using single-cell transcriptional analysis and cultures of fetal liver precursor cells, Bendelac and colleagues define the divergence of these cells.

Regulatory T (T_reg) cells have a distinct cellular metabolism compared to effector T cells. Chi and colleagues show that autophagy is required to maintain the functional integrity and metabolic homeostasis of T_reg cells in the face of inflammatory environmental cues.

SHARPIN is a component of the linear-ubiquitin-chain–assembly complex that positively regulates activation of the transcription factor NF-κB. Liu and colleagues show that SHARPIN regulates TCR signaling independently of NF-κB and that its deficiency impairs T_reg cell generation.

Inflammation can boost antigen-specific adaptive immune responses. Ziegler and colleagues show that type I interferon-mediated inflammation can also affect bystander naive CD4⁺ T cells by transiently increasing their expression of Foxp3, which might limit aggressive responses against self-antigens.

T cell anergy is a well-established phenomenon, but its physiological role is unclear. Mueller and colleagues demonstrate that anergic self-reactive T cells are present at steady state and that these are predisposed to generate peripheral regulatory T cells.

T cells proliferate in response to cues provided by antigen-presenting cells or high concentrations of cytokines. Krummel and colleagues reveal a distinct requirement for the cytoskeletal protein septin 7 for cytokine-driven bystander T cell proliferation.

The transcription factor Blimp-1 is required for the differentiation of activated B cells into plasmablasts. Nutt and colleagues show that plasma cells need Blimp-1 to maintain antibody production by regulating the kinase mTOR and unfolded-protein-response pathways.

Blimp-1 is known to act as a transcriptional repressor by suppressing genes associated with mature and activated germinal center B cells. Busslinger and colleagues show that Blimp-1 can also directly activate gene expression in plasma cells, including those encoding proteins that regulate the production of membrane-bound immunoglobulin versus secreted immunoglobulin.