Issues

Duncan et al. and Bastard et al. identify a loss-of-function IFNAR1 common in western Polynesians and a loss-of-function IFNAR2 allele in Inuits.

IL-17 promotes collagen deposition by cancer-associated fibroblasts and enhances immune exclusion of tumors.

Véronique Dartois and Thomas Dick discuss the evolution of drug discovery for the treatment of nontuberculous mycobacterial pulmonary disease (NTM-PD).

Reporting the distribution and inclusion of both males and females in immunology and infectious diseases research is improving, but rigorous analyses of differential outcomes between males and females, including mechanistic inquiries into the causes of sex differences, still lags behind.

Sex differences in immune function have important implications for autoimmune disease susceptibility and prognosis. This review highlights sex differences in immune health and focuses on the genetic and epigenetic mechanisms contributing to the female bias of autoimmune rheumatic disease.

There is a growing appreciation for the vastness of neutrophil functional states in cancer. Quail et al. provide a consensus statement on mechanisms governing neutrophil heterogeneity in the context of malignancy and discuss controversies and solutions in neutrophil research.

Glycosylation alterations are a hallmark of pancreatic cancer. This review discusses the contributions of aberrant glycosylation to protumorigenic signaling, metastasis, and remodeling the tumor immune microenvironment in pancreatic cancer.

CD36 functions as both a signaling receptor and fatty acid transporter in various immune and non-immune cells. This review summarizes how its dual functions determine immune cell functions and fates, which contribute to common diseases including atherosclerosis and tumor progression.

Local inflammation spreads to remote positions via sensory neuron–interneuron crosstalk using ATP. This neural pathway, or remote inflammation gateway reflex, may be a therapeutic target for inflammatory diseases with remote inflammation, such as rheumatoid arthritis.

The authors report a novel form of autosomal recessive IFNAR2 deficiency due to a null and common allele in Arctic populations, broadening its clinical phenotype from diseases caused by live-attenuated viral vaccines to include life-threatening influenza and SARS-CoV-2.

Bastard et al. report a loss-of-function IFNAR1 variant that is surprisingly common (allele frequency >1%) in individuals of western Polynesian ancestry, while it is absent or extremely rare elsewhere. Homozygotes for this allele are prone to severe viral diseases.

This study uncovers a novel mechanism whereby IL-17 signaling drives immune exclusion by activating a HIF1α-mediated collagen deposition program in cancer-associated fibroblasts in murine skin tumor models.

Antigen stimulation induces a subset of CD4⁺ and CD8⁺ T cells to differentiate into CD4⁺CD8⁺ T cell subsets gaining in polyfunctional characteristics within the tumor. Monitoring CD4⁺CD8⁺ T cells may thus favor the identification and selection of antigen-reactive T cells to drive clinical benefit.

How intratumoral T cell subsets differ in their recruitment or retention is unclear. In this study, photoconversion is used to temporally label tumor-infiltrating lymphocytes, revealing the continuous migration of TCF-1⁺ T cells between the tumor and draining lymphoid tissue.

B_ND cells demonstrate phenotypical and functional changes indicative of a loss of anergy with severe SARS-CoV-2 infection, and these changes correlate with increased systemic inflammation and autoreactive antibodies. Together, this data suggests that viral infection relaxes peripheral B cell tolerance.

Yao et al. describe GIMAP6 deficiency in humans and mice showing immune dysfunction and susceptibility to bacterial infections. They find impaired autophagy in GIMAP6-deficient immune cells and define a functional complex composed of GIMAP6, GIMAP7, and GABARAPL2.

Using induced pluripotent stem cells carrying CDC42^R186C, trapping of CDC42 C-terminal variants within the Golgi apparatus is shown to trigger autoinflammation by promoting pyrin inflammasome assembly through a mechanism independent of their GTPase activity.

Hypoxia in club cells in the lung epithelium induces increased ILC2 responses, leading to enhanced inflammation and immunity. The mechanism, revealed by VHL deletion, is increased HIF2α driving the secretion of adrenomedullin, which activates ILC2.

Kanbar et al. show that the long noncoding RNA Malat1 impacts the differentiation of effector and memory CD8⁺ T cell subsets by virtue of preferential epigenetic repression of memory-associated genes in terminal effector cells through an interaction with Ezh2.

Neuroimmune interaction influences essential CNS processes. Hanuscheck et al. report on the expression of interleukin-4 receptor alpha at presynaptic terminals in mouse and the human brain. The modulation of neuronal IL-4R signaling alters the neuronal transcriptome, impacts synaptic transmission, and causes anxiety-related behavior.