Single-nucleus RNA sequencing of human periventricular white matter in vascular dementia.

Vascular dementia (VaD) refers to a variety of dementias driven by cerebrovascular disease and is the second leading cause of dementia globally. VaD may be caused by ischemic strokes, intracerebral hemorrhage, and/or cerebral small vessel disease, commonly identified as white matter hyperintensities on MRI. The mechanisms underlying these white matter lesions in the periventricular brain are poorly understood.

Role of Inflammatory Processes in Hemorrhagic Stroke.

Hemorrhagic stroke is the deadliest form of stroke and includes the subtypes of intracerebral hemorrhage and subarachnoid hemorrhage. A common cause of hemorrhagic stroke in older individuals is cerebral amyloid angiopathy. Intracerebral hemorrhage and subarachnoid hemorrhage both lead to the rapid collection of blood in the central nervous system and generate inflammatory immune responses that involve both brain resident and infiltrating immune cells.

Inflammatory Responses After Ischemic Stroke.

Ischemic stroke generates an immune response that contributes to neuronal loss as well as tissue repair. This is a complex process involving a range of cell types and effector molecules and impacts tissues outside of the CNS. Recent reviews address specific aspects of this response, but several years have passed and important advances have been made since a high-level review has summarized the overall state of the field.

PD-L1-PD-1 interactions limit effector regulatory T cell populations at homeostasis and during infection.

Phenotypic and transcriptional profiling of regulatory T (T) cells at homeostasis reveals that T cell receptor activation promotes T cells with an effector phenotype (eT) characterized by the production of interleukin-10 and expression of the inhibitory receptor PD-1. At homeostasis, blockade of the PD-1 pathway results in enhanced eT cell activity, whereas during infection with Toxoplasma gondii, early interferon-γ upregulates myeloid cell expression of PD-L1 associated with reduced T cell populations. In infected mice, blockade of PD-L1, complete deletion of PD-1 or lineage-specific deletion of PD-1 in T cells prevents loss of eT cells.

Divergent Functions of Tissue-Resident and Blood-Derived Macrophages in the Hemorrhagic Brain.

Background And Purpose: Brain tissue-resident microglia and monocyte-derived macrophages (MDMs) are innate immune cells that contribute to the inflammatory response, phagocytosis of debris, and tissue repair after injury. We have previously reported that both microglia and MDMs transition from proinflammatory to reparative phenotypes over days after an intracerebral hemorrhage (ICH). However, their individual functional properties in the brain remain largely unknown.

Leukocyte dynamics after intracerebral hemorrhage in a living patient reveal rapid adaptations to tissue milieu.

Intracerebral hemorrhage (ICH) is a devastating form of stroke with a high mortality rate and few treatment options. Discovery of therapeutic interventions has been slow given the challenges associated with studying acute injury in the human brain. Inflammation induced by exposure of brain tissue to blood appears to be a major part of brain tissue injury.

Loss of IL-27Rα Results in Enhanced Tubulointerstitial Fibrosis Associated with Elevated Th17 Responses.

Clinical and experimental studies have established that immune cells such as alternatively activated (M2) macrophages and Th17 cells play a role in the progression of chronic kidney disease, but the endogenous pathways that limit these processes are not well understood. The cytokine IL-27 has been shown to limit immune-mediated pathology in other systems by effects on these cell types, but this has not been thoroughly investigated in the kidney. Unilateral ureteral obstruction was performed on wild-type and IL-27Rα mice.

Impact of Interleukin-27p28 on T and B Cell Responses during Toxoplasmosis.

Interleukin-27 (IL-27) is a heterodimeric cytokine composed of the subunits IL-27p28 and EBi3, and while the IL-27 heterodimer influences T cell activities, there is evidence that IL-27p28 can have EBi3-independent activities; however, their relevance to infection is unclear. Therefore, the studies presented here compared how IL-27p28 transgenics and IL-27p28 mice responded to the intracellular parasite While the loss of IL-27p28 and its overexpression both result in increased susceptibility to , the basis for this phenotype reveals distinct roles for IL-27p28. As a component of IL-27, IL-27p28 is critical to limit infection-induced T cell-mediated pathology, whereas the ectopic expression of IL-27p28 reduced the effector T cell population and had a major inhibitory effect on parasite-specific antibody titers and a failure to control parasite replication in the central nervous system.

IL-27 and TCR Stimulation Promote T Cell Expression of Multiple Inhibitory Receptors.

Inhibitory receptors (IR) are a diverse group of cell surface molecules that modulate T cell activation, but there are gaps in our knowledge of the cell-extrinsic factors that regulate their expression. The present study found that in vivo overexpression of IL-27 in mice led to increased T cell expression of PD-L1, LAG-3, TIGIT, and TIM-3. In vitro, TCR stimulation alone promoted expression of multiple IRs, whereas IL-27 alone induced expression of PD-L1.

Cytokine- and TCR-Mediated Regulation of T Cell Expression of Ly6C and Sca-1.

Ly6C and Sca-1 (Ly6A/E) are Ly6 family GPI-anchored surface molecules that are differentially expressed by multiple immune populations. Ly6C expression has been used to distinguish short-lived effector CD4 T cells from memory precursor effector cells, whereas Sca-1 has been used in the identification of CD8 memory stem cells. This study examines the expression patterns of these molecules and establishes that, in vitro, IL-27, type I IFN, and IFN-γ are potent inducers of Ly6C and Sca-1 in naive mouse CD4 and CD8 T cells, whereas TGF-β limits their expression.

A phenotypically and functionally distinct human T2 cell subpopulation is associated with allergic disorders.

Allergen-specific type 2 helper T (T2) cells play a central role in initiating and orchestrating the allergic and asthmatic inflammatory response pathways. One major factor limiting the use of such atopic disease-causing T cells as both therapeutic targets and clinically useful biomarkers is the lack of an accepted methodology to identify and differentiate these cells from overall nonpathogenic T2 cell types. We have described a subset of human memory T2 cells confined to atopic individuals that includes all allergen-specific T2 cells.

IL-27 Limits Type 2 Immunopathology Following Parainfluenza Virus Infection.

Respiratory paramyxoviruses are important causes of morbidity and mortality, particularly of infants and the elderly. In humans, a T helper (Th)2-biased immune response to these infections is associated with increased disease severity; however, little is known about the endogenous regulators of these responses that may be manipulated to ameliorate pathology. IL-27, a cytokine that regulates Th2 responses, is produced in the lungs during parainfluenza infection, but its role in disease pathogenesis is unknown.

Endothelial cells are a replicative niche for entry of Toxoplasma gondii to the central nervous system.

An important function of the blood-brain barrier is to exclude pathogens from the central nervous system, but some microorganisms benefit from the ability to enter this site. It has been proposed that Toxoplasma gondii can cross biological barriers as a motile extracellular form that uses transcellular or paracellular migration, or by infecting a host cell that then crosses the blood-brain barrier. Unexpectedly, analysis of acutely infected mice revealed significant numbers of free parasites in the blood and the presence of infected endothelial cells in the brain vasculature.

Myeloid cell microsomal prostaglandin E synthase-1 fosters atherogenesis in mice.

Microsomal prostaglandin E synthase-1 (mPGES-1) in myeloid and vascular cells differentially regulates the response to vascular injury, reflecting distinct effects of mPGES-1-derived PGE2 in these cell types on discrete cellular components of the vasculature. The cell selective roles of mPGES-1 in atherogenesis are unknown. Mice lacking mPGES-1 conditionally in myeloid cells (Mac-mPGES-1-KOs), vascular smooth muscle cells (VSMC-mPGES-1-KOs), or endothelial cells (EC-mPGES-1-KOs) were crossed into hyperlipidemic low-density lipoprotein receptor-deficient animals.

Specific immunotherapy modifies allergen-specific CD4(+) T-cell responses in an epitope-dependent manner.

Background: Understanding the mechanisms by which the immune system induces and controls allergic inflammation at the T-cell epitope level is critical for the design of new allergy vaccine strategies.

Objective: We sought to characterize allergen-specific T-cell responses linked with allergy or peripheral tolerance and to determine how CD4(+) T-cell responses to individual allergen-derived epitopes change over allergen-specific immunotherapy.

Methods: Timothy grass pollen (TGP) allergy was used as a model for studying grass pollen allergies.

T cell development requires constraint of the myeloid regulator C/EBP-α by the Notch target and transcriptional repressor Hes1.

Notch signaling induces gene expression of the T cell lineage and discourages alternative fate outcomes. Hematopoietic deficiency in the Notch target Hes1 results in severe T cell lineage defects; however, the underlying mechanism is unknown. We found here that Hes1 constrained myeloid gene-expression programs in T cell progenitor cells, as deletion of the myeloid regulator C/EBP-α restored the development of T cells from Hes1-deficient progenitor cells.

CD4+ T cells recognize unique and conserved 2009 H1N1 influenza hemagglutinin epitopes after natural infection and vaccination.

Influenza A/California/4/2009 (H1N1/09) is a recently emerged influenza virus capable of causing serious illness or death in otherwise healthy individuals. Serious outcomes were most common in young adults and children, suggesting that pre-existing heterologous immunity may influence the severity of infection. Using tetramers, we identified CD4(+) T-cell epitopes within H1N1/09 hemagglutinin (HA) that share extensive homology with seasonal influenza and epitopes that are unique to H1N1/09 HA.

Frequency of epitope-specific naive CD4(+) T cells correlates with immunodominance in the human memory repertoire.

The frequency of epitope-specific naive CD4(+) T cells in humans has not been extensively examined. In this study, a systematic approach was used to examine the frequency of CD4(+) T cells that recognize the protective Ag of Bacillus anthracis in both anthrax vaccine-adsorbed vaccinees and nonvaccinees with HLA-DRB1*01:01 haplotypes. Three epitopes were identified that had distinct degrees of immunodominance in subjects that had received the vaccine.

Differentiation stage determines pathologic and protective allergen-specific CD4+ T-cell outcomes during specific immunotherapy.

Background: The main obstacle to elucidating the role of CD4(+) T cells in allergen-specific immunotherapy (SIT) has been the absence of an adequately sensitive approach to directly characterize rare allergen-specific T cells without introducing substantial phenotypic modifications by means of in vitro amplification.

Objective: We sought to monitor, in physiological conditions, the allergen-specific CD4(+) T cells generated during natural pollen exposure and during allergy vaccination.

Methods: Alder pollen allergy was used as a model for studying seasonal allergies.

Ara h 1-reactive T cells in individuals with peanut allergy.

Background: Effective immunotherapy for peanut allergy is hampered by a lack of understanding of peanut-reactive CD4(+) T cells.

Objective: To identify, characterize, and track Ara h 1-reactive cells in subjects with peanut allergy by using Ara h 1-specific class II tetramers.

Methods: Tetramer-guided epitope mapping was used to identify the antigenic peptides within the peanut allergen Ara h 1.