Volume 23 Issue 5, May 2022

A genetic recorder of T cell replicative history identifies fewer accumulated divisions in a subset of CD8⁺ central memory T cells that shows stem-cell-like quiescence and superior recall capacity.

Thomas and colleagues describe how multiple mRNA vaccine boosters, with or without natural SARS-CoV-2 infection, shape T cell immunity.

LAG3 interferes with TCR signaling by lowering the pH in the vicinity of the TCR and inducing dissociation of the key signaling kinase Lck from the co-receptors CD8 and CD4.

The activation of the noncanonical NLRP3 inflammasome can be elicited by the interaction and interdependent activation of caspase-11 and NLRP3 that follows coincident cytosolic detection of lipopolysaccharide and bacterial mRNA from live Gram-negative bacteria.

A role for mitochondrial ATP that leads to phosphocreatine and the subsequent generation of cytosolic ATP via creatine kinase B is now proposed in the activation of the NLRP3 inflammasome.

Switching the CD4 and CD8 coreceptor proteins encoded in Cd4 and Cd8 loci results in a reversed T cell immune system, with CD4⁺ cytotoxic T cells and CD8⁺ helper T cells. Thus, whichever coreceptor is encoded in Cd4 promotes a helper lineage fate, and whichever is encoded in Cd8 promotes a cytotoxic lineage fate.

A new genetic ‘recorder’ of long-term cell proliferation revealed substantial heterogeneity in the division history of central memory CD8⁺ T cells. Importantly, the extent of past proliferation was related to distinct transcriptional features and re-expansion potential, highlighting an unappreciated division of labor within the central memory T cell pool.

Enormous progress has been made in the ten years since immune checkpoint blockade (ICB) was first approved for treating melanoma. Zappasodi and Huang review the current state of the art of ICB for melanoma and prospects for the future.

The transcription factor TCF-1 has multiple roles during T cell development and in mature T cells. Gounari and Khazaie review the potential mechanisms by which TCF-1 regulates gene expression.

Cassatella and colleagues identify CD66b⁻CD64^dimCD115⁻ cells in the human bone marrow as the earliest neutrophil-committed progenitor cells described to date.

How the mitochondrial electron transport chain (ETC) interacts with the NLRP3 inflammasome is somewhat unclear. Here the authors use individual complex inhibitors and new genetic models to show that ETC is critical in providing ATP via the phosphocreatine shuttle to activate the NLRP3 inflammasome.

Blander and colleagues show that concurrent detection of LPS and bacterial RNA triggers the interaction of procaspase-11 with NLRP3, upstream of the activation of either receptor and before NLRP3–ASC oligomerization.

How ILC1s respond to cancer cells is somewhat controversial. Here, the authors show that IFNγ released by ILC1s can control acute myeloid leukemia by promoting leukemia stem cell apoptosis and favoring their differentiation into non-leukemic cells.

To determine how T cell lineage fates are determined in the thymus, Singer and colleagues generated ‘FlipFlop’ mice with a functionally reversed T cell immune system that distinguishes TCR signal strength versus TCR signal duration.

Perry et al. demonstrate that regulatory T (T_reg) cell function is restrained by the cell-autonomous action of the checkpoint inhibitor molecule PD-1. This PD-1-dependent mechanism tunes T_reg cell function during homeostasis and infection.

Vignali and colleagues show that the inhibitory receptor LAG3 interferes with TCR signaling and T cell activation by lowering the pH at the immune synapse, which causes the dissociation of the tyrosine kinase Lck from the CD4 or CD8 co-receptor.

Wragg and colleagues use MHC class II tetramers and TCRβ sequencing to track clonal populations of spike-specific CD4⁺ cT_FH cells from cohorts of convalescent individuals with coronavirus disease 2019 or SARS-CoV-2-vaccinated individuals over 15 months.

Thomas and colleagues describe how multiple SARS-CoV-2 antigen exposures, including mRNA vaccine boosters, primary infection and breakthrough infection, shape T cell immunity.

Schumacher and colleagues have designed a reporter system that allows in vivo tracking of replicative history over many cell generations. Using this system to study acute T cell responses, they uncover substantial diversity in past division of central memory CD8⁺ T cells and its link to cell state and recall potential.

Malek and colleagues describe the longitudinal transcriptional and epigenetic changes occurring in regulatory T cells following in vivo stimulation with IL-2 or the biologic IL-2–CD25.