Volume 23 Issue 9, September 2022

A key biochemical event that enables T cells to discriminate between TCR antigens of varying affinities and to respond only to high-affinity antigens is full activation of the kinase ZAP70.

ETS1 regulates tissue-remodeling properties of specific fibroblast subtypes in the synovium, gut and cancer and thus emerges as a novel cross-tissue therapeutic target for modulation of pathogenic fibroblast activation.

The inhibitory checkpoint molecule CTLA-4 is essential for regulatory T cell function. A new study highlights the differential manner in which CTLA-4 binds CD80 and CD86, which determines its cellular fate and orchestrates immune tolerance regulation.

The net effect of type I interferon (IFN-I) signaling on tumor control depends on various factors, including the potential engagement of adaptive anticancer immunity. New findings delineate a targetable epigenetic mechanism by which suboptimal IFN-I signaling promotes tumor progression in the context of cancer stem cell expansion and immunoevasion.

Tissue-destructive fibroblasts in arthritis are driven by the transcription factor ETS1. Analysis of a cross-tissue, single-cell fibroblast dataset and genetic loss-of-function approaches further suggest that ETS1-expressing fibroblasts have a universal role in pathological tissue remodeling in multiple diseases, including arthritis, colitis and cancer.

Intestinal group 3 innate lymphoid (ILC3) cells exhibit increased mobility in response to flagellin-mediated inflammation. This ‘patrolling’ behavior promotes IL-22 diffusion and prevents intestinal epithelial cell death. Enhanced ILC3 dynamics rely on environmental cues and suggest a prominent ILC3 tissue adaptation that reinforces intestinal barrier integrity.

Through access to healthy donors’ bronchoalveolar lavage (BAL) samples cryopreserved before the COVID-19 pandemic, we discovered CD4⁺ and CD8⁺ T cells able to cross-recognize SARS-CoV-2 among the airway tissue-resident memory pool. Pre-pandemic donors with detectable SARS-CoV-2-cross-reactive T cells in their airways also had stronger immunity to human seasonal coronaviruses.

The role of eosinophils in response to cancer is not well understood. Here the authors document evidence that eosinophils contribute to the immune response to cancer and to immunotherapies and postulate that these cells might be more important than expected in these contexts.

Serafini and colleagues show that intestinal villus ILC3s, which are largely immotile at steady state, develop a patrolling behavior in response to inflammation.

Maini and colleagues used bronchoalveolar lavage (BAL) samples from the lower respiratory tract of healthy donors obtained before the COVID-19 pandemic to show airway-resident cross-reactive T cells are present in pre-pandemic BAL, and correlated with the strength of human coronavirus immunity

Osteoclastic bone destruction is mediated by factors such as RANKL elaborated by tissue-destructive fibroblasts. Takayanagi and colleagues identify the transcription factor Ets1 as a major regulator of these pathogenic cells.

The STAT3 pathway is activated in B cells by interleukin-6 and interleukin-21; however, methylation of Lys140 prevents its dephosphorylation and deactivation. Yin et al. report a noncanonical role for the histone demethylase Jmjd1c in demethylating phosphorylated STAT3, thereby terminating B cell activation and limiting plasma cell generation and potential B cell-mediated autoimmunity.

Roncagalli and colleagues use time-resolved high-throughput proteomic analyses to provide a comprehensive picture of the impact of ligand affinity on early T cell receptor signaling.

The inhibitory receptor CTLA-4 recognizes two ligands on opposing antigen-presenting cells, CD80 and CD86. Sansom and colleagues show CTLA-4 captures ligands by transendocytosis, whereupon low-affinity CD86 releases CTLA-4 at low pH to promote CTLA-4 recycling; however, high-affinity CD80 remains bound and targets CTLA-4 for ubiquitination and destruction.

Type I interferons have been described to have protumor or antitumor functions depending on context. Here the authors show a protumor function for type I interferons in that they promote cancer stem cells by upregulating the chromatin remodeling factor KDM1B.