ON THE COVER
Durand et al. describe how human cDC2 and macrophages induce Tfh responses. The cover shows a human tonsil section analyzed by imaging mass cytometry, using DNA intercalator staining and merged signals from membrane markers to detect individual cells. See page 1561.
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People & Ideas
Place and Kanneganti review the role of pyroptosis and necroptosis in driving inflammatory diseases, current cytokine blockade therapies, and the potential benefits of targeting the executioners of lytic cell death.
Brief Definitive Reports
Tissue residence of motile lymphocytes depends on systems that counteract egress-promoting cues. Laidlaw et al. find that the migration inhibitory S1PR2 receptor cooperates with CD69 to promote the retention of IL-17–producing γδ T cells within the dermis.
The anti-CD81 mAb (5A6) eliminates lymphoma tumor cells from patient follicular biopsy specimens while sparing the imbedded normal B and T lymphocytes. It has equivalent therapeutic effects as rituximab against a xenografted human B cell lymphoma.
Singh et al. show that MYC affects mRNA translation efficiency and start-site selection. Notable examples include the translation of mRNAs encoding most proteins of the electron transport chain and aberrant translation initiation site usage in the CD19 receptor that allows escape from CD19-directed CAR-T therapy.
Novel anti–PD-1 antibodies (Abs) not blocking the PD-1–PDL-1 interaction are presented with equivalent antagonistic activity to classical blocking anti–PD-1 Abs and have distinct mechanisms of action that synergize in functional recovery of exhausted CD8 T cells and enhancing tumor suppression in an immunogenic mouse tumor model.
Sex-specific effects of microbiome perturbations on cerebral Aβ amyloidosis and microglia phenotypes
An antibiotic cocktail leads to reductions in brain amyloidosis, altered morphology, and gene expression in microglia of male but not female transgenic mice that exhibit Aβ deposits. The microbiome plays a causal role in modulating Aβ burden and microglia phenotypes.
Which antigen-presenting cells are involved in Tfh responses in humans remains unclear. Durand et al. show that human tonsil cDC2 and CD14+ macrophages provide Tfh polarizing signals to CD4+ T cells in distinct locations within tonsil, playing sequential roles in Tfh induction.
Sphingosine 1-phosphate receptor-1 signaling via the Gi pathway is suppressed by lysophosphatidic acid receptor-1, which recruits β-arrestin to the heterotypic receptor complex. This mechanism occurs at sinus lining lymphatic endothelial cells of lymph nodes and modulates complex cell–cell junction structure.
Hlf marks the developmental pathway for hematopoietic stem cells but not for erythro-myeloid progenitors
Hematopoietic stem cells (HSCs) and HSC-independent progenitors are generated from hemogenic endothelium. Yokomizo et al. show that Hlf expression distinguishes nascent HSCs from HSC-independent progenitors. HSC specification, regulated by the Evi-1/Hlf axis, is activated only within Hlf+ nascent hematopoietic clusters.
EndoS from Streptococcus pyogenes hydrolyzes the functionally important glycan on the Fc portion of IgG during infections in humans. In mice with IgG mediated immunity against the M1 protein on the bacteria, EndoS is a virulence factor.
Nakai et al. show that the COMMD3/8 complex functions as an adaptor that selectively recruits GRK6 to chemoattractant receptors and promotes B cell migration and humoral immune responses.
Using mouse models, we showed that CtIP is essential for early B cell development, but not the survival of naive B cells. T847 and T859 phosphorylation have distinct role development and end-processing in B cells.
The E3 ligase VHL promotes follicular helper T cell differentiation via glycolytic-epigenetic control
Zhu et al. demonstrate that the VHL–HIF-1α axis plays an important role during the initiation of Tfh cells through glycolytic-epigenetic reprogramming. The downstream player, GAPDH, impairs Tfh cell development by decreasing icos expression through regulation of m6A modification.
Mielke et al. show that TCF-1 limits IL-17–producing CD8+ T (Tc17) cell development from double-positive thymocytes through the sequential suppression of MAF and RORγt, while cementing conventional CD8+ T cell fate.
von Gamm et al. demonstrate that mice deficient for the RNase Regnase-3 (Zc3h12c) develop hypertrophic lymph nodes and a systemic interferon response. Regnase-3 is a functional RNase that acts in myeloid cells upon IRF signaling, suggesting it to be an evolutionary counterpart to Regnase-1.