Immunopeptidomics Mapping of Listeria monocytogenes T Cell Epitopes in Mice.

Listeria monocytogenes is a foodborne intracellular bacterial model pathogen. Protective immunity against Listeria depends on an effective CD8 T cell response, but very few T cell epitopes are known in mice as a common animal infection model for listeriosis. To identify epitopes, we screened for Listeria immunopeptides presented in the spleen of infected mice by mass spectrometry-based immunopeptidomics.

Dynamic landscapes and protective immunity coordinated by influenza-specific lung-resident memory CD8 T cells revealed by intravital imaging.

Lung-tissue-resident memory (T) CD8 T cells are critical for heterosubtypic immunity against influenza virus (IAV) reinfection. How T cells surveil the lung, respond to infection, and interact with other cells remains unresolved. Here, we used IAV infection of mice in combination with intravital and static imaging to define the spatiotemporal dynamics of lung T cells before and after recall infection.

Regenerating murine CD8+ lung tissue resident memory T cells after targeted radiation exposure.

Radiation exposure occurs during medical procedures, nuclear accidents, or spaceflight, making effective medical countermeasures a public health priority. Naïve T cells are highly sensitive to radiation-induced depletion, although their numbers recover with time. Circulating memory CD8+ T cells are also depleted by radiation; however, their numbers do not recover.

Discrete class I molecules on brain endothelium differentially regulate neuropathology in experimental cerebral malaria.

Cerebral malaria is the deadliest complication that can arise from Plasmodium infection. CD8 T-cell engagement of brain vasculature is a putative mechanism of neuropathology in cerebral malaria. To define contributions of brain endothelial cell major histocompatibility complex (MHC) class I antigen-presentation to CD8 T cells in establishing cerebral malaria pathology, we developed novel H-2Kb LoxP and H-2Db LoxP mice crossed with Cdh5-Cre mice to achieve targeted deletion of discrete class I molecules, specifically from brain endothelium.

Sublethal whole-body irradiation induces permanent loss and dysfunction in pathogen-specific circulating memory CD8 T cell populations.

The increasing use of nuclear energy sources inevitably raises the risk of accidental or deliberate radiation exposure and associated immune dysfunction. However, the extent to which radiation exposure impacts memory CD8 T cells, potent mediators of immunity to recurring intracellular infections and malignancies, remains understudied. Using P14 CD8 T cell chimeric mice (P14 chimeras) with an lymphocytic choriomeningitis virus (LCMV) infection model, we observed that sublethal (5Gy) whole-body irradiation (WBI) induced a rapid decline in the number of naive (T) and P14 circulating memory CD8 T cells (T), with the former being more susceptible to radiation-induced numeric loss.

CD4 T Cell-Dependent and -Independent Roles for IFN-γ in Blood-Stage Malaria.

Production of IFN-γ by CD4 T cells is widely theorized to control Plasmodium parasite burden during blood-stage malaria. Surprisingly, the specific and crucial mechanisms through which this highly pleiotropic cytokine acts to confer protection against malarial disease remain largely untested in vivo. Here we used a CD4 T cell-restricted Cre-Lox IFN-γ excision mouse model to test whether and how CD4 T cell-derived IFN-γ controls blood-stage malaria.

AIM2 sensors mediate immunity to infection in hepatocytes.

Malaria, caused by parasites is a severe disease affecting millions of people around the world. undergoes obligatory development and replication in the hepatocytes, before initiating the life-threatening blood-stage of malaria. Although the natural immune responses impeding infection and development in the liver are key to controlling clinical malaria and transmission, those remain relatively unknown.

Expeditious recruitment of circulating memory CD8 T cells to the liver facilitates control of malaria.

Circulating memory CD8 T cell trafficking and protective capacity during liver-stage malaria infection remains undefined. We find that effector memory CD8 T cells (Tem) infiltrate the liver within 6 hours after malarial or bacterial infections and mediate pathogen clearance. Tem recruitment coincides with rapid transcriptional upregulation of inflammatory genes in Plasmodium-infected livers.

Cutting Edge: Subunit Booster Vaccination Confers Sterilizing Immunity against Liver-Stage Malaria in Mice Initially Primed with a Weight-Normalized Dose of Radiation-Attenuated Sporozoites.

Radiation-attenuated sporozoite (RAS) vaccination offers hope for global malaria control through induction of protective liver-stage-specific memory CD8 T cells. Effective RAS vaccination regimens exist; however, widespread implementation remains unfeasible. A key difficulty resides in the need to administer three or more doses i.

p53 Hinders CRISPR/Cas9-Mediated Targeted Gene Disruption in Memory CD8 T Cells In Vivo.

CRISPR/Cas9 technology has revolutionized rapid and reliable gene editing in cells. Although many cell types have been subjected to CRISPR/Cas9-mediated gene editing, there is no evidence of success in genetic alteration of Ag-experienced memory CD8 T cells. In this study, we show that CRISPR/Cas9-mediated gene editing in memory CD8 T cells precludes their proliferation after Ag re-encounter in vivo.

Peripherally induced brain tissue-resident memory CD8 T cells mediate protection against CNS infection.

The central nervous system (CNS) is classically viewed as immune-privileged; however, recent advances highlight interactions between the peripheral immune system and CNS in controlling infections and tissue homeostasis. Tissue-resident memory (T) CD8 T cells in the CNS are generated after brain infections, but it is unknown whether CNS infection is required to generate brain T cells. We show that peripheral infections generate antigen-specific CD8 memory T cells in the brain that adopt a unique T signature.

Protective role for the N-terminal domain of α-dystroglycan in Influenza A virus proliferation.

α-Dystroglycan (α-DG) is a highly glycosylated basement membrane receptor that is cleaved by the proprotein convertase furin, which releases its N-terminal domain (α-DGN). Before cleavage, α-DGN interacts with the glycosyltransferase LARGE1 and initiates functional O-glycosylation of the mucin-like domain of α-DG. Notably, α-DGN has been detected in a wide variety of human bodily fluids, but the physiological significance of secreted α-DGN remains unknown.

Monocyte-Derived CD11c Cells Acquire Plasmodium from Hepatocytes to Prime CD8 T Cell Immunity to Liver-Stage Malaria.

Plasmodium sporozoites inoculated by mosquitoes migrate to the liver and infect hepatocytes prior to release of merozoites that initiate symptomatic blood-stage malaria. Plasmodium parasites are thought to be restricted to hepatocytes throughout this obligate liver stage of development, and how liver-stage-expressed antigens prime productive CD8 T cell responses remains unknown. We found that a subset of liver-infiltrating monocyte-derived CD11c cells co-expressing F4/80, CD103, CD207, and CSF1R acquired parasites during the liver stage of malaria, but only after initial hepatocyte infection.

Memory CD8 T cells mediate severe immunopathology following respiratory syncytial virus infection.

Memory CD8 T cells can provide protection from re-infection by respiratory viruses such as influenza and SARS. However, the relative contribution of memory CD8 T cells in providing protection against respiratory syncytial virus (RSV) infection is currently unclear. To address this knowledge gap, we utilized a prime-boost immunization approach to induce robust memory CD8 T cell responses in the absence of RSV-specific CD4 T cells and antibodies.

A T Cell Receptor Locus Harbors a Malaria-Specific Immune Response Gene.

Immune response (Ir) genes, originally proposed by Baruj Benacerraf to explain differential antigen-specific responses in animal models, have become synonymous with the major histocompatibility complex (MHC). We discovered a non-MHC-linked Ir gene in a T cell receptor (TCR) locus that was required for CD8 T cell responses to the Plasmodium berghei GAP50 epitope in mice expressing the MHC class I allele H-2D. GAP50-specific CD8 T cell responses emerged from a very large pool of naive Vβ8.

Suppression of autoimmune demyelinating disease by preferential stimulation of CNS-specific CD8 T cells using Listeria-encoded neuroantigen.

CD8 T-cells predominate in CNS lesions of MS patients and display oligoclonal expansion. However, the role of myelin-specific CD8 T-cells in disease remains unclear, with studies showing protective and pathogenic roles in EAE. We demonstrated a disease-suppressive function for CNS-specific CD8 T-cells in a model where the antigen is exogenously administered in vivo and used for in vitro activation.

Context-dependent effects of SOCS3 in angiotensin II-induced vascular dysfunction and hypertension in mice: mechanisms and role of bone marrow-derived cells.

Carotid artery disease is a major contributor to stroke and cognitive deficits. Angiotensin II (Ang II) promotes vascular dysfunction and disease through mechanisms that include the IL-6/STAT3 pathway. Here, we investigated the importance of suppressor of cytokine signaling 3 (SOCS3) in models of Ang II-induced vascular dysfunction.

Discriminating Protective from Nonprotective Plasmodium-Specific CD8+ T Cell Responses.

Despite decades of research, malaria remains a global health crisis. Current subunit vaccine approaches do not provide efficient long-term, sterilizing immunity against Plasmodium infections in humans. Conversely, whole parasite vaccinations with their larger array of target Ags have conferred long-lasting sterilizing protection to humans.

Inflammatory IL-15 is required for optimal memory T cell responses.

Due to their ability to rapidly proliferate and produce effector cytokines, memory CD8+ T cells increase protection following reexposure to a pathogen. However, low inflammatory immunizations do not provide memory CD8+ T cells with a proliferation advantage over naive CD8+ T cells, suggesting that cell-extrinsic factors enhance memory CD8+ T cell proliferation in vivo. Herein, we demonstrate that inflammatory signals are critical for the rapid proliferation of memory CD8+ T cells following infection.

Paradoxical Increase in Mortality and Rupture of Intracranial Aneurysms in Microsomal Prostaglandin E2 Synthase Type 1-Deficient Mice: Attenuation by Aspirin.

Background: Inflammation plays an important role in formation and rupture of intracranial aneurysms. Expression of microsomal prostaglandin E2 (PGE2) synthase type 1 (mPGES-1) is increased in the wall of intracranial aneurysms in humans. PGE2, a by-product of mPGES-1, is associated with inflammation and cerebrovascular dysfunction.

Lung airway-surveilling CXCR3(hi) memory CD8(+) T cells are critical for protection against influenza A virus.

Inducing memory CD8(+) T cells specific for conserved antigens from influenza A virus (IAV) is a potential strategy for broadly protective vaccines. Here we show that memory CD8(+) T cells in the airways played an important role in early control of IAV. Expression of the chemokine receptor CXCR3 was critical for memory CD8(+) T cells to populate the airways during the steady state and vaccination approaches were designed to favor the establishment of memory CD8(+) T cells in the airways.

Aged mice exhibit a severely diminished CD8 T cell response following respiratory syncytial virus infection.

Respiratory virus infections in the elderly result in increased rates of hospitalization and death. Respiratory syncytial virus (RSV) is a leading cause of severe virus-induced respiratory disease in individuals over the age of 65. CD8 T cells play a critical role in mediating RSV clearance.

In vivo CD8+ T cell dynamics in the liver of Plasmodium yoelii immunized and infected mice.

Plasmodium falciparum malaria remains one of the most serious health problems globally and a protective malaria vaccine is desperately needed. Vaccination with attenuated parasites elicits multiple cellular effector mechanisms that lead to Plasmodium liver stage elimination. While granule-mediated cytotoxicity requires contact between CD8+ effector T cells and infected hepatocytes, cytokine secretion should allow parasite killing over longer distances.