Astrocytes in aging.

The mammalian nervous system is impacted by aging. Aging alters brain architecture, is associated with molecular damage, and can manifest with cognitive and motor deficits that diminish the quality of life. Astrocytes are glial cells of the CNS that regulate the development, function, and repair of neural circuits during development and adulthood; however, their functions in aging are less understood.

Suppression of astrocyte BMP signaling improves fragile X syndrome molecular signatures and functional deficits.

Fragile X syndrome (FXS) is a monogenic neurodevelopmental disorder with manifestations spanning molecular, neuroanatomical, and behavioral changes. Astrocytes contribute to FXS pathogenesis and show hundreds of dysregulated genes and proteins; targeting upstream pathways mediating astrocyte changes in FXS could therefore be a point of intervention. To address this, we focused on the bone morphogenetic protein (BMP) pathway, which is upregulated in FXS astrocytes.

Protocol for the purification and transcriptomic analysis of mouse astrocytes using GFAT.

Astrocytes are glial cells of the central nervous system that modulate neuronal function. Here, we present glyoxal-fixed astrocyte nuclei transcriptomics (GFAT), a protocol for the purification and transcriptomic analysis of astrocyte nuclei from the cortex and cerebellum of adult and aged fresh mouse brain. We describe steps for tissue dissection, glyoxal fixation, homogenization, nuclei isolation, antibody staining, fluorescence-activated cell sorting, and RT-qPCR or bulk RNA sequencing.

Early transcriptional and epigenetic divergence of CD8+ T cells responding to acute versus chronic infection.

During a microbial infection, responding CD8+ T cells give rise to effector cells that provide acute host defense and memory cells that provide sustained protection. An alternative outcome is exhaustion, a state of T cell dysfunction that occurs in the context of chronic infections and cancer. Although it is evident that exhausted CD8+ T (TEX) cells are phenotypically and molecularly distinct from effector and memory CD8+ T cells, the factors regulating the earliest events in the differentiation process of TEX cells remain incompletely understood.

BAtCHing stem-like T cells during exhaustion.

Long-term pathogen and tumor control as well as checkpoint immunotherapies rely on ‘stem-like’ CD8 T cells. New results uncover BACH2 as a key regulator of this subpopulation and solve an important piece of the puzzle.

TCRα reporter mice reveal contribution of dual TCRα expression to T cell repertoire and function.

It is known that a subpopulation of T cells expresses two T cell receptor (TCR) clonotypes, though the extent and functional significance of this is not established. To definitively evaluate dual TCRα cells, we generated mice with green fluorescent protein and red fluorescent protein reporters linked to TCRα, revealing that ∼16% of T cells express dual TCRs, notably higher than prior estimates. Importantly, dual TCR expression has functional consequences, as dual TCR cells predominated response to lymphocytic choriomeningitis virus infection, comprising up to 60% of virus-specific CD4 and CD8 T cells during acute responses.

CD8 T cells drive anorexia, dysbiosis, and blooms of a commensal with immunosuppressive potential after viral infection.

Infections elicit immune adaptations to enable pathogen resistance and/or tolerance and are associated with compositional shifts of the intestinal microbiome. However, a comprehensive understanding of how infections with pathogens that exhibit distinct capability to spread and/or persist differentially change the microbiome, the underlying mechanisms, and the relative contribution of individual commensal species to immune cell adaptations is still lacking. Here, we discovered that mouse infection with a fast-spreading and persistent (but not a slow-spreading acute) isolate of lymphocytic choriomeningitis virus induced large-scale microbiome shifts characterized by increased Verrucomicrobia and reduced Firmicute/Bacteroidetes ratio.

Type I IFNs and CD8 T cells increase intestinal barrier permeability after chronic viral infection.

Intestinal barrier leakage constitutes a potential therapeutic target for many inflammatory diseases and represents a disease progression marker during chronic viral infections. However, the causes of altered gut barrier remain mostly unknown. Using murine infection with lymphocytic choriomeningitis virus, we demonstrate that, in contrast to an acute viral strain, a persistent viral isolate leads to long-term viral replication in hematopoietic and mesenchymal cells, but not epithelial cells (IECs), in the intestine.

An Unusual MHC Molecule Generates Protective CD8+ T Cell Responses to Chronic Infection.

The CD8+ T cell response to the intracellular parasite varies dramatically between mouse strains, resulting in stark differences in control of the parasite. Protection in BALB/c mice can be attributed to an unusually strong and protective MHC-1 L-restricted CD8+ T cell response directed against a peptide derived from the parasite antigen GRA6. The MHC-1 L molecule has limited peptide binding compared to conventional MHC molecules such as K or D, which correlates with polymorphisms associated with "elite control" of HIV in humans.

TLR9 Sensing of Self-DNA Controls Cell-Mediated Immunity to Listeria Infection via Rapid Conversion of Conventional CD4 T Cells to T.

CD4 T lymphocytes are crucial for controlling a range of innate and adaptive immune effectors. For CD8 cytotoxic T lymphocyte (CTL) responses, CD4 T cells can function as helpers (T) to amplify magnitude and functionality or as regulatory cells (T) capable of profound inhibition. It is unclear what determines differentiation to these phenotypes and whether pathogens provoke alternate programs.

Dangerously Fit: Extracellular ATP Aids Memory T Cell Metabolism.

In a recent issue of Nature, Borges da Silva et al. (2018) reveal that P2RX7, a receptor for extracellular ATP, promotes CD8 T cell memory by enhancing metabolic fitness. This work links an ancient "danger" signal with long-term immunity.

TGF-β receptor maintains CD4 T helper cell identity during chronic viral infections.

Suppression of CD8 and CD4 T cells is a hallmark in chronic viral infections, including hepatitis C and HIV. While multiple pathways are known to inhibit CD8 T cells, the host molecules that restrict CD4 T cell responses are less understood. Here, we used inducible and CD4 T cell-specific deletion of the gene encoding the TGF-β receptor during chronic lymphocytic choriomeningitis virus infection in mice, and determined that TGF-β signaling restricted proliferation and terminal differentiation of antiviral CD4 T cells.