Volume 21 Issue 8, August 2020

Casey Weaver recounts how his group’s discovery of the T_H17 pathway resolved several conundrums that had arisen in the wake of the original T_H1–T_H2 hypothesis.

In October 2005, we, alongside the laboratory of Casey Weaver, identified a third type of helper T cells that produce the cytokine IL-17, important for the regulation of tissue inflammation.

CAR T cells are engineered to recognize tumor-specific antigens and kill tumor cells. A study of CAR T cell activation using single-molecule microscopy reveals that CARs fail to efficiently convert antigen binding into early T cell signaling events.

A new report finds that peripheral immunization generates tissue-resident memory CD8⁺ T cells in the central nervous system that provide robust protection against local infection.

Quantitative systems-level proteomics is cleverly used to reveal a dynamic program of protein turnover in naive and memory CD4⁺ T cells that, alongside a stockpile of metabolic protein machinery, poises the cells for activation.

Guanylate-binding proteins (GBPs) promote immune defenses against infectious agents. Two studies reveal that GBP1 directly binds to cytosolic lipopolysaccharide (LPS), bringing caspase-4 to the surface of bacteria to induce pyroptosis.

Antigen escape by solid tumors has limited the efficacy of genetically modified T cells. T cells engineered to secrete the cytokine Flt3L induce the activation of endogenous T cells, enabling a broader repertoire of tumor antigens to be targeted via the expansion of intratumoral antigen presenting cells, significantly improving tumor responses.

Evolutionary genetic and experimental analyses suggest that mutations causing familial Mediterranean fever have been positively selected in the Middle East, probably because they confer heightened resistance against Yersinia pestis infection.

In this Review, Smyth and colleagues provide an overview of recent advances in NK cell biology and discuss the progress and problems of NK cell–based cancer immunotherapies.

Huppa and colleagues highlight signaling deficiencies in chimeric antigen receptor (CAR)-modified T cells that limit the efficacy of CAR T cell therapies to target tumors with diminished antigen expression.

Familial Mediterranean fever is an autoinflammatory disease caused by gain-of-function mutations in the pyrin inflammasome. Kastner and colleagues show that mutant pyrin better resists suppression by the plague bacterium Yersinia pestis and may have been positively selected in human Middle Eastern populations.

STING ER exit is the rate-limiting step in STING signaling, but the mechanism that drives this process is not understood. Paludan and colleagues identify CxORF56, called STEEP here, as a positive regulator of STING signaling.

How lipopolysaccharide embedded in bacterial membranes is sensed by intracellular defense mechanisms has been puzzling. Randow and colleagues show that guanylate-binding proteins assemble on the surface of Gram-negative bacteria to initiate downstream pyroptosis.

Takayanagi and colleagues show that the chromatin remodeler Chd4 works with both Fezf2 and Aire to promote promiscuous tissue-restricted antigen expression in medullary thymic epithelial cells, mediating central tolerance in the thymus.

How Lck is recruited to the TCR to initiate signaling is not well known. Here Minguet and colleagues report a previously unknown binding motif in the CD3ε cytoplasmic tail that interacts in a noncanonical mode with the Lck SH3 domain that may help to improve TCR activation and the antitumor activity of a clinically approved CAR.

Immunoselection underpins tumor antigenic variability and is a key impediment to adoptive cell therapies. Darcy, Beavis and colleagues use T cells engineered to express the dendritic cell growth factor Flt3L to co-opt the host endogenous adaptive immune response and control experimental tumor models.

Geiger and colleagues use SILAC and mass spectrometry to study protein turnover in human T cells and examine how naive T cells maintain their quiescence and transition to activated cells.

Harty and colleagues show that peripheral infections can establish and maintain functional antigen-specific tissue-resident memory CD8⁺ T cells in the central nervous system.

Ten–eleven translocation (Tet) enzymes oxidize 5-methylcytosine, facilitating DNA demethylation. Kurosaki and colleagues show that B cell–specific loss of Tet2 and Tet3 leads to lupus-like autoimmunity in mice, in part through increased B cell expression of CD86 and enhanced activation of CD4⁺ T cells.