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.

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.

Cryopreservation of Sporozoites.

Malaria is a deadly disease caused by the parasite, , and impacts the lives of millions of people around the world. Following inoculation into mammalian hosts by infected mosquitoes, the sporozoite stage of undergoes obligate development in the liver before infecting erythrocytes and causing clinical malaria. The most promising vaccine candidates for malaria rely on the use of attenuated live sporozoites to induce protective immune responses.

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.

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.

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.

Impact of acute malaria on pre-existing antibodies to viral and vaccine antigens in mice and humans.

Vaccine-induced immunity depends on long-lived plasma cells (LLPCs) that maintain antibody levels. A recent mouse study showed that Plasmodium chaubaudi infection reduced pre-existing influenza-specific antibodies--raising concerns that malaria may compromise pre-existing vaccine responses. We extended these findings to P.

Perforin plays an unexpected role in regulating T-cell contraction during prolonged Listeria monocytogenes infection.

After infection or vaccination, antigen-specific T cells proliferate then contract in numbers to a memory set point. T-cell contraction is observed after both acute and prolonged infections although it is unknown if contraction is regulated similarly in both scenarios. Here, we show that contraction of antigen-specific CD8(+) and CD4(+) T cells is markedly reduced in TNF/perforin-double deficient (DKO) mice responding to attenuated Listeria monocytogenes infection.

The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited.

During the past ten years, dramatic advances have been made in unraveling the biological bases of age-related macular degeneration (AMD), the most common cause of irreversible blindness in western populations. In that timeframe, two distinct lines of evidence emerged which implicated chronic local inflammation and activation of the complement cascade in AMD pathogenesis. First, a number of complement system proteins, complement activators, and complement regulatory proteins were identified as molecular constituents of drusen, the hallmark extracellular deposits associated with early AMD.

Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: characterization, ethnic distribution and evolutionary implications.

Background: Variants in the complement factor H gene (CFH) are associated with age-related macular degeneration (AMD). CFH and five CFH-related genes (CFHR1-5) lie within the regulators of complement activation (RCA) locus on chromosome 1q32. Aims and Methods.

Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration.

Age-related macular degeneration (AMD) is the most common form of irreversible blindness in developed countries. Variants in the factor H gene (CFH, also known as HF1), which encodes a major inhibitor of the alternative complement pathway, are associated with the risk for developing AMD. Here we test the hypothesis that variation in genes encoding other regulatory proteins of the same pathway is associated with AMD.

Extended haplotypes in the complement factor H (CFH) and CFH-related (CFHR) family of genes protect against age-related macular degeneration: Characterization, ethnic distribution and evolutionary implications.

Background: Variants in the complement factor H gene (CFH) are associated with age-related macular degeneration (AMD). CFH and five CFH-related genes (CFHR1-5) lie within the regulators of complement activation (RCA) locus on chromosome 1q32.

Aims And Methods: In this study, the structural and evolutionary relationships between these genes and AMD was refined using a combined genetic, molecular and immunohistochemical approach.

A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration.

Age-related macular degeneration (AMD) is the most frequent cause of irreversible blindness in the elderly in developed countries. Our previous studies implicated activation of complement in the formation of drusen, the hallmark lesion of AMD. Here, we show that factor H (HF1), the major inhibitor of the alternative complement pathway, accumulates within drusen and is synthesized by the retinal pigmented epithelium.