Volume 24 Issue 8, August 2023

Despite the absence of MHC class II molecules on tumor cells, stem-cell-like CD4⁺ T cells specific for tumor neoantigens can mediate profound antitumor effects by licensing antigen-presenting cells and augmenting antitumor CD8⁺ T cells in the tumor microenvironment and draining lymph nodes.

CD8⁺ virtual memory T cells have been studied mainly for their antimicrobial functions but it seems that their descendants can contribute to inflammation and hair loss in the context of alopecia areata.

Naive B cells activated during infection enter the germinal center (GC) reaction, in which high-affinity antibodies are generated. A new study has uncovered a distinct metabolic requirement for B cells poised to undergo the GC reaction, whose activation required lactate dehydrogenase A-dependent aerobic glycolysis.

Bronchus-associated lymphoid tissue (BALT), which develops in the lung during infancy before declining over childhood, supports localized immune reactions against airway infections in early life including the generation of germinal center-like B cells specific for respiratory pathogens.

Confusion exists as to whether transitional dendritic cells are a bone fide subset or just a transitional state, as the name indicates. New data are complicating matters further by showing some interesting heterogeneity in these cells.

Delineation of the steps that lead to immune-related adverse effects indicates that checkpoint-mediated suppression of autoreactive T cells occurs within peripheral target tissues rather than at the point of lymph node activation.

We have used human-derived stem cells to generate various microglial states and investigate the function of human microglia in a scalable manner. We were able to model disease-associated microglia that replicated transcriptional signatures found in human tissue, and further developed a lentiviral transfer system to manipulate human microglial states in vitro.

Susceptibility to respiratory pathogens is increased during early life, yet children can mount highly effective immune responses to novel pathogens in the absence of a fully developed immune system. We found that bronchus-associated lymphoid tissue (BALT) develops in the lungs early in life and supports germinal center formation and B cell differentiation to produce antibodies specific for respiratory pathogens, revealing a mechanism for immune protection in an as-yet-undeveloped immune system.

The mechanisms by which T_H17 cells can either protect barrier tissues or initiate autoimmunity remain unknown. Here we identify the transcription factor EGR2 as a key determinant of T_H17 cell pathogenicity. EGR2 was found to govern T_H17 cell migration, regulate the expression of pathogenicity-associated genes, and facilitate the recruitment of other immune cells in the central nervous system.

Tumor cells exploit G-protein-coupled receptor (GPCR) signaling networks to promote angiogenesis, grow and metastasize. We show that tumor cells leverage a GPCR–Gα_s–protein kinase A (PKA) signaling axis to polarize CD8⁺ T cells into a dysfunctional state, thereby limiting the tumor infiltration and cytotoxic function of these cells and reducing the efficacy of current immunotherapies.

Lloyd and Saglani review the immunology of early-life respiratory infections and how developmental immunity determines lifelong lung health.

Nimmerjahn and colleagues review posttranslational modification of immunoglobulins and how these posttranslational modifications influence antibody effector function. Furthermore, they discuss the implications of immunoglobulin posttranslational modifications when designing therapeutic antibodies for various clinical indications.

Huang and colleagues show that METTL3-mediated m⁶A mRNA modifications support the transcriptional activity of activated ILC2s.

Establishment of antiviral immune responses depends on dendritic cells (DCs), but how transitional DCs compare with other DC subsets in this regard is unclear. Here the authors show the origins of these cells and their proinflammatory function during viral infection.

Tolar and colleagues describe how differential expression of CR2 by spatially distinct follicular dendritic cells regulates antigen retention in germinal centers of draining lymph nodes.

Basu et al. find that the transcription factor ThPOK is not restricted to T cells, as it also is expressed in myeloid cell progenitors and contributes to the lineage choice of monocyte-dendritic cells as opposed to neutrophils.

Virtual memory T cells have antimicrobial functions but whether they can contribute to inflammatory pathology is unclear. Here the authors show that a subset of CD8⁺ T cells that originates from virtual memory T cells upon cytokine stimulation can drive the chronic inflammatory disease alopecia areata via innate-like cytotoxic effector functions.

Here, the authors use computational screening and a chemogenetic analysis of transgenic mice to show that Gα_s-coupled G-protein-coupled receptors on exhausted CD8⁺ T cells are involved in suppression of effector functions and inhibition of the protective effects of immune checkpoint immunotherapy.

Lazarevic and colleagues show that the transcription factor EGR2 controls a transcriptional program specific to pathogenic T_H17 cells in the CNS.

In cancer, neoantigen (NeoAg)-specific CD8⁺ T cells capable of direct tumor recognition have been extensively studied but little is known of the role of NeoAg-specific CD4⁺ T cells. Here Schoenberger and colleagues analyze an oligoclonal CD4⁺ T cell response to a naturally arising murine tumor NeoAg at the level of TCR usage and functionality.

Sharma et al. identify an early metabolic checkpoint dependent upon lactate dehydrogenase for newly activated B cells to enter germinal centers.

Young children frequently encounter respiratory pathogens that elicit immune responses in developing lungs. Farber and colleagues examine rare lung tissue samples obtained from pediatric organ donors and find age-dependent formation of bronchus-associated lymphoid tissue (BALT), which peaks at 3 years of age and dissipates thereafter. Profiling of BALT lymphocytes indicates that repertoire and functional differences exist between the lung, draining lymph nodes and circulating cells.

Stevens and colleagues show that human stem-cell-differentiated microglia can be used to model the extensive transcriptional diversity of human brain microglia.