The Chemokine Receptor CXCR6 Is Required for the Maintenance of Liver Memory CD8+ T Cells Specific for Infectious Pathogens

Tse, Sze Wah; Radtke, Andrea J.; Espinosa, Diego A.; Cockburn, Ian A.; Zavala, Fidel

doi:10.1093/infdis/jiu281

Cited by 138 publications

(155 citation statements)

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“…It is possible Vδ2 + T cells also mediate direct effector functions in the liver. A high frequency of circulating γδ T cells express CXCR6, a chemokine receptor that facilitates surveillance of the liver sinusoids 22 , and produce IFN-γ and perforin ( Supplementary Fig. 7i-m), two potent effector molecules shown to mediate killing of intracellular Pf.…”

Section: Discussionmentioning

confidence: 99%

Protection against malaria at 1 year and immune correlates following PfSPZ vaccination

Ishizuka¹,

Lyke²,

DeZure³

et al. 2016

Nat Med

318

371

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In 2015 there were an estimated 214 million clinical cases and 438,000 deaths due to malaria 1 , primarily caused by Pf in children in sub-Saharan Africa. A highly effective vaccine is urgently needed to prevent malaria in individuals and to facilitate elimination of malaria from defined geographic areas. To achieve these goals, we established an interim target of >85% sterile protection against Pf infection for >6 months 2 .There is currently no malaria subunit vaccine that approaches this level of protection. The most extensively studied candidate malaria vaccine, RTS,S (a subunit vaccine based on the Pf circumsporozoite protein (PfCSP)), confers sterilizing protection against controlled human malaria infection (CHMI) in about 22% of healthy malarianaive adults 5 months after vaccination 3 . In a phase 3 field study, the efficacy of RTS,S against clinical malaria was 26% and 36% in young infants and children between the ages of 5 and 17 months, respectively, through 38-48 months of follow-up following a fourdose regimen on a 0-, 1-, 2-, and 20-month schedule 4 . Therefore, it is necessary to investigate alternative vaccination strategies that confer long-lived sterilizing protection 5,6 .Sustained sterilizing immunity against the pre-erythrocytic stages of Pf has been observed in humans immunized by wholeparasite approaches using mosquitoes for vaccination 7,8 . In a study An attenuated Plasmodium falciparum (Pf) sporozoite (SPZ) vaccine, PfSPZ Vaccine, is highly protective against controlled human malaria infection (CHMI) 3 weeks after immunization, but the durability of protection is unknown. We assessed how vaccine dosage, regimen, and route of administration affected durable protection in malaria-naive adults. After four intravenous immunizations with 2.7 × 10 5 PfSPZ, 6/11 (55%) vaccinated subjects remained without parasitemia following CHMI 21 weeks after immunization. Five non-parasitemic subjects from this dosage group underwent repeat CHMI at 59 weeks, and none developed parasitemia. Although Pf-specific serum antibody levels correlated with protection up to 21-25 weeks after immunization, antibody levels waned substantially by 59 weeks. Pf-specific T cell responses also declined in blood by 59 weeks.To determine whether T cell responses in blood reflected responses in liver, we vaccinated nonhuman primates with PfSPZ Vaccine. Pf-specific interferon-g-producing CD8 T cells were present at ~100-fold higher frequencies in liver than in blood. Our findings suggest that PfSPZ Vaccine conferred durable protection to malaria through long-lived tissue-resident T cells and that administration of higher doses may further enhance protection.

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Section: Discussionmentioning

confidence: 99%

Protection against malaria at 1 year and immune correlates following PfSPZ vaccination

Ishizuka¹,

Lyke²,

DeZure³

et al. 2016

Nat Med

318

371

View full text Add to dashboard Cite

show abstract

“…For example, eliciting large numbers of T cells is only the first step. These T cells must then home to the liver and establish a liver-resident memory population for effective immunity [38]. Once in the liver, all T-cell targets may not be created equally as the T cell-hepatocyte physical interaction required for killing may be restricted by the liver architecture.…”

Section: Challenges For Pe Vaccine Developmentmentioning

confidence: 99%

“…Studies in mice have shown that a liver-resident memory T-cell population is essential for PE immunity [38]. However, T-cell assays to identify human clinical correlates of protection are limited, relying exclusively on sampling PBMCs and assessing phenotypes with or without antigenic stimulation (e.g., intracellular cytokine staining).…”

Section: The Current State Of Clinical Pe Vaccine Development: Chmi Tmentioning

confidence: 99%

“…This is not an accurate model of the complex journey that sporozoites take in traversing multiple cell types in the skin, transiting through the circulation and again traversing multiple cell types in the complex 3D structure of the liver before establishing infection in a hepatocyte. While one trial has correlated inhibition of invasion in vitro to protection following RAS immunization in vivo [44], it remains to be seen if this is true for other vaccination methods.Studies in mice have shown that a liver-resident memory T-cell population is essential for PE immunity [38]. However, T-cell assays to identify human clinical correlates of protection are limited, relying exclusively on sampling PBMCs and assessing phenotypes with or without antigenic stimulation (e.g., intracellular cytokine staining).…”

mentioning

confidence: 99%

“…Antibody and T-cell responses can be probed independently by immunizations in animals either lacking or transiently depleted of relevant effector molecules or cells (e.g., Aid -/-mice which lack B cells, depleting T cells using monoclonal antibodies (mAbs) or depleting complement via cobra venom factor). Several studies have pointed to a critical role for liver-resident T cells in an effective immune response elicited by liver-stage antigens [38,44,48], while antibody responses appear to mainly function in preventing access of sporozoites to hepatocytes [62,63]. Small animal models can thus facilitate a more thorough and mechanistic investigation of PE vaccine-induced immunity by assessing the ability of candidate vaccines to activate distinct arms of the immune system and the relative contribution of each to protection.…”

mentioning

confidence: 99%

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An Expanding Toolkit for Preclinical Pre-Erythrocytic Malaria Vaccine Development: Bridging Traditional Mouse Malaria Models and Human Trials

2016

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Malaria remains a significant public health burden with 214 million new infections and over 400,000 deaths in 2015. Elucidating relevant Plasmodium parasite biology can lead to the identification of novel ways to control and ultimately eliminate the parasite within geographic areas. Particularly, the development of an effective vaccine that targets the clinically silent pre-erythrocytic stages of infection would significantly augment existing malaria elimination tools by preventing both the onset of blood-stage infection/disease as well as spread of the parasite through mosquito transmission. In this Perspective, we discuss the role of small animal models in pre-erythrocytic stage vaccine development, highlighting how human liver-chimeric and human immune system mice are emerging as valuable components of these efforts. Malaria continues to cause significant morbidity and mortality despite renewed and concerted efforts to eliminate the causative agents, parasites of the genus Plasmodium. These efforts have largely focused on control of the Anopheles mosquito vectors, and antimalarial drug treatment of symptomatic infected individuals. The 214 million new malaria infections and 438,000 deaths due to malaria in 2015 were disproportionately borne by low income countries where malaria is endemic, and declines in malaria infections since 2000 have been slowest in countries with low resource availability and high malaria burden [1]. In the fight against malaria, effective vaccines preventing both disease and transmission will be important tools to achieve WHO goals of a 90% reduction in disease burden by 2030 [1,2]. In humans, malaria is caused predominantly by the parasite species Plasmodium falciparum and Plasmodium vivax, with the remainder of infections caused by three additional parasite species, Plasmodium malariae, Plasmodium ovale and Plasmodium knowlesi [1].Malaria parasite transmission occurs when a Plasmodium-infected Anopheles mosquito bites and by probing the skin for a blood meal, deposits motile sporozoite stages into the host. Sporozoites pass through the dermis using active motility, enter a capillary and then rapidly home to the liver. Once in the liver sporozoites enter the parenchyma and infect hepatocytes, wherein they then transmogrify into liver stages, which grow, replicate and ultimately differentiate into tens of thousands of first-generation merozoites. Merozoites of human malaria parasites emerge from the liver into the blood stream 7-10 days after transmission, where they undergo cyclic erythrocytic infection and intraerythrocytic replication. This blood-stage infection is responsible for all mortality and clinical symptoms of malaria, as well as infection of a new mosquito vector by sexual stage parasites for onward transmission [3,4]. Stages prior to blood-stage infection (i.e., the sporozoite and liver stages) are collectively known as preerythrocytic (PE) stages of infection and vaccine candidates targeting these stages are collectively termed PE vaccines. By preventing progression to ...

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Host Genetic Impact on Infectious Diseases among Different Ethnic Groups

Naidoo,

Arumugam,

Ramsuran

2023

Advanced Genetics

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Infectious diseases such as malaria, tuberculosis (TB), human immunodeficiency virus (HIV), and the coronavirus disease of 2019 (COVID‐19) are problematic globally, with high prevalence particularly in Africa, attributing to most of the death rates. There have been immense efforts toward developing effective preventative and therapeutic strategies for these pathogens globally, however, some remain uncured. Disease susceptibility and progression for malaria, TB, HIV, and COVID‐19 vary among individuals and are attributed to precautionary measures, environment, host, and pathogen genetics. While studying individuals with similar attributes, it is suggested that host genetics contributes to most of an individual's susceptibility to disease. Several host genes are identified to associate with these pathogens. Interestingly, many of these genes and polymorphisms are common across diseases. This paper analyzes genes and genetic variations within host genes associated with HIV, TB, malaria, and COVID‐19 among different ethnic groups. The differences in host–pathogen interaction among these groups, particularly of Caucasian and African descent, and which gene polymorphisms are prevalent in an African population that possesses protection or risk to disease are reviewed. The information in this review could potentially help develop personalized treatment that could effectively combat the high disease burden in Africa.

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The Chemokine Receptor CXCR6 Is Required for the Maintenance of Liver Memory CD8+ T Cells Specific for Infectious Pathogens

Cited by 138 publications

References 32 publications

Protection against malaria at 1 year and immune correlates following PfSPZ vaccination

Protection against malaria at 1 year and immune correlates following PfSPZ vaccination

An Expanding Toolkit for Preclinical Pre-Erythrocytic Malaria Vaccine Development: Bridging Traditional Mouse Malaria Models and Human Trials

Host Genetic Impact on Infectious Diseases among Different Ethnic Groups

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