Volume 23 Issue 11, November 2022

DNSe, a double-negative thymocyte-specific Notch1 enhancer, is essential for activation of Notch1 expression and has a central role in T-cell-lineage commitment during the earliest stages of thymocyte development.

Clonal expansion and immunological memory of lymphocytes provide protective immunity against repeated pathogen exposure in mammals. New technologies are enabling the investigation of these intricate processes, focusing on human natural killer cells during human cytomegalovirus infection.

CD40 has long been known as a co-stimulatory molecule involved in T cell help for dendritic cells, and thereby as a contributor to CD8⁺ T cell immunity against cancers and infections. However, CD40 signaling drives complex functional responses that can contribute to tumor-specific CD8⁺ T cell responses in unexpected ways.

Effective vaccines elicit neutralizing antibodies and long-lasting memory, but this can be challenging with some pathogens, such as HIV. A new study shows how a slow-delivery protein immunization strategy administered in dose-escalation format over 12 days increased the durability of germinal centers and improved immunological outcomes.

By combining single-cell mRNA sequencing and a genetic pulse–chase mouse model, we identified multiple subsets of mouse long-lived plasma cells and showed that these cells can originate from diverse developmental routes.

A stage-specific enhancer augments Notch1 signaling from the early thymic progenitor (ETP) through double-negative thymocyte stages. Enhanced Notch1 activity is required for T cell lineage differentiation at the later end of this developmental interval, but Notch1 also suppresses precocious T lineage commitment in ETPs and promotes their expansion as multi-lineage progenitors.

We identified the transmembrane protein CMTM4 as an essential component of the IL-17 receptor. CMTM4 is required for membrane expression of IL-17 receptor subunit C and activation of IL-17A pro-inflammatory signaling. Lack of CMTM4 largely protects mice from experimental psoriasis, which suggests that targeting CMTM4 might alleviate IL-17-mediated autoimmunity.

Godbout and colleagues discuss the neuroimmune mechanisms that underlie social-stress defeat, anxiety, and post-traumatic stress disorder.

CD40 is typically understood as a costimulatory molecule. Here, the authors show CD4⁺ T cell-induced CD40 signaling in conventional type 1 dendritic cells results in complicated gene expression that can enhance CD8⁺ T cell priming by various underappreciated and independent mechanisms.

Here, the authors use single-cell multiomics and profiling of mitochondrial mutations as endogenous barcodes to show that human adaptive NK cells induced by CMV persist as clonal expansions that inherit clone-specific epigenetic profiles.

Durable antibody-mediated responses require long-lived plasma cells; however, these cells are difficult to identify. Hai Qi and colleagues now phenotypically identify these cells and show their heterogeneity.

Lai and colleagues show that the RNA helicase DDX5 mediates the alternative splicing of the IL-36R mRNA in keratinocytes and modulates skin inflammation downstream of IL-17D signaling.

Wen and colleagues show that the transmembrane protein SUSD2 is a specific negative regulator of CD8⁺ T cells activation in the tumor environment by interacting with IL-2 receptor α and interfering with IL-2 binding to the receptor.

Wherry and colleagues provide a comparative analysis of paired single-cell RNA-sequencing and single-cell assay for transposase-accessible chromatin sequencing profiles of CD8⁺ T cells in acute and chronic lymphocytic choriomeningitis virus infections, identifying new features about T_ex cell subsets and epigenetic differences from acutely infected precursors seen at early time points in infection.

Daniel, Yost, Hsiung, et al. generate a single-cell multiomic atlas of T cell exhaustion in chronic viral infection, which reveals molecular programs of exhausted T cell subsets, identifies divergent clonal exhausted T cell differentiation trajectories and nominates TCR signal strength as a driver of clonal fate.

Notch signaling is required for T cell development. Georgopoulos and colleagues identify an enhancer that specifically boosts Notch1 expression in early thymic progenitors through the DN3 stage, expanding the less committed multipotent progenitors and preparing these cells for faithful lineage commitment.

Draber and colleagues show that the tetra-transmembrane protein CMTM4 is a subunit of the IL-17 receptor.