ON THE COVER
The cover shows a spleen section immunostained for CD4 (dark blue), IgD (magenta), and GL7 (light blue) from mice that recovered from Plasmodium yoelii NL infection on day 35 aft er infection. Image © Lee at al., 2021. https://doi.org/10.1084/jem.20211336
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mTEC damage risks immune recovery
Alawam et al. demonstrate in this issue that prolonged damage in thymic medullary epithelial cells causes the failure in self-tolerance in newly generated T cells and provokes post-transplant autoimmunity.
Playing dirty with virus transmission
Fay et al. investigate viral infection dynamics by cohousing dirty pet store mice and rats with clean laboratory mice.
Bhlhe40: Gatekeeper of the GC
The generation of high-affinity antibodies in the germinal center (GC) requires interplay between GC B cells and T follicular helper cells. Rauschmeier et al. report that Bhlhe40 restrains GC output through distinct regulatory roles in both arms of the response.
Goldilocks and the three TILs
Shakiba et al. show that TCR signal strength determines T cell differentiation and function in tumors.
How to induce protective humoral immunity against Plasmodium falciparum circumsporozoite protein
Antibodies against Plasmodium falciparum circumsporozoite protein (PfCSP) can protect from malaria. However, the efficacy of anti-PfCSP vaccine responses is limited. This review summarizes our molecular and cellular understanding of humoral anti-PfCSP immune responses and discusses implications for vaccine design.
Brief Definitive Reports
Failures in thymus medulla regeneration during immune recovery cause tolerance loss and prime recipients for auto-GVHD
The thymus ensures immune tolerance by synchronizing thymocyte development and selection. Alawam et al. show that a functional uncoupling of these events occurs after bone marrow transplantation, which results in post-transplant tolerance loss and autoimmunity caused by selective failures in thymus medulla regeneration.
Trav15-dv6 family Tcrd rearrangements diversify the Tcra repertoire
Dauphars et al. show that prior Tcrd rearrangement is essential for a combinatorially diverse Tcra repertoire in mouse thymocytes. Trav15-dv6 family Tcrd rearrangements are critical for Tcra repertoire formation because of their central and distal locations in the Vα-Vδ array.
Targeting PLD2 in adipocytes augments adaptive thermogenesis by improving mitochondrial quality and quantity in mice
Kim et al. find that phospholipase D2 deficiency increases thermogenic program and improves mitochondrial quality in adipose tissues leading to resistance to high fat diet–induced obesity and insulin resistance. Thus, targeting PLD2 may offer therapeutics for obese and/or type 2 diabetic patients.
Intravenous administration of BCG protects mice against lethal SARS-CoV-2 challenge
BCG when administered by the intravenous but not subcutaneous route provides protection against lethal SARS-CoV-2 infection in mice, reducing immunopathology in addition to viral load and thus providing an experimental model for delineating innate mechanisms of resistance against COVID-19.
Technical Advances and Resources
Systems-level conservation of the proximal TCR signaling network of mice and humans
Nicolas et al. exploited traceable gene tagging in primary human T cells to establish at the systems level the composition and dynamics of TCR-induced signalosomes. It provides a decision-support tool accelerating definition of the mechanism of action of drugs targeting T cells.
Natural rodent model of viral transmission reveals biological features of virus population dynamics
Viruses are diverse and ubiquitous, but many infection models do not recapitulate natural transmission and evolution. Here we bridge natural and experimental systems to study real-time transmission dynamics within and between hosts, identify novel viruses, and infer virus–pathogen relationships.
Bhlhe40 function in activated B and TFH cells restrains the GC reaction and prevents lymphomagenesis
The transcription factor Bhlhe40 restrains the germinal center reaction through cell-intrinsic functions in both activated B cells and T follicular helper cells. The absence of Bhlhe40 results in a dysregulated germinal center response and lymphomagenesis.
TCR signal strength defines distinct mechanisms of T cell dysfunction and cancer evasion
TCR signal strength determines T cell differentiation and function in tumors, with high-signal-strength interactions resulting in dysfunction and low-signal-strength interactions resulting in functional inertness. Fine-tuning TCR signal strength to an intermediate range improves anti-tumor activity in vivo.
TIM3+TRBV11-2 T cells and IFNγ signature in patrolling monocytes and CD16+ NK cells delineate MIS-C
MIS-C is a novel immunodysregulation syndrome in children with a history of SARS-CoV-2 infection. This study employs a multi-omics approach to explore its immunopathogenesis. The authors show that IFNγ-mediated interactions between T cells, monocytes, and NK cells reside at the heart of the disease.
CD127 imprints functional heterogeneity to diversify monocyte responses in inflammatory diseases
Zhang et al. analyzed human monocytes in acute and chronic inflammatory disease conditions with multiomics approaches and identified a subset of CD127+ hypoinflammatory monocytes within the inflammatory environment, uncovering functional heterogeneity of human inflammatory monocytes imprinted by CD127.
B cell–intrinsic TBK1 is essential for germinal center formation during infection and vaccination in mice
This study identifies an unexpected role of TBK1 as a crucial B cell–intrinsic factor for germinal center (GC) formation. TBK1 in Pre-GC determines B cell fate to promote long-lasting humoral immunity during malaria and vaccination.
Transition from cMyc to L-Myc during dendritic cell development coordinated by rising levels of IRF8
In vivo reporter analysis of myeloid progenitor populations identifies the precise stage at which Myc expression switches to Mycl expression during dendritic cell development. Genetic analysis reveals that this switch is controlled in part by the transcription factor IRF8.
CD116+ fetal precursors migrate to the perinatal lung and give rise to human alveolar macrophages
Evren et al. identify CD116+ fetal liver cells as precursors of human alveolar macrophages in early life and determine the impact of cell origin on lung macrophage identity and function in the human context with a unique in vivo model.
The transcription factor HIF-1α mediates plasticity of NKp46+ innate lymphoid cells in the gut
Krzywinska et al. have studied the impact of the transcription factor HIF-1α on the phenotype of intestinal NKp46+ innate lymphoid cells and how it affects gut homeostasis.
Lipid-loaded tumor-associated macrophages sustain tumor growth and invasiveness in prostate cancer
Integration of human single-cell RNA sequencing and mouse data on prostate cancer identifies a population of tumor-associated macrophages that is engulfed with lipids. The scavenger receptor Marco mediates lipid intake, and lipid accumulation in turn confers to macrophages’ protumor features.
Lung tumor MHCII immunity depends on in situ antigen presentation by fibroblasts
Kerdidani et al. show that immunological hot spots in lung tumors are sustained by fibroblasts. Lung fibroblasts present MHCII cancer antigens locally and at the same time prevent CD4 T cells from apoptosis by activating the complement receptor C1qbp.
Correction: Thyrotropin aggravates atherosclerosis by promoting macrophage inflammation in plaques