Summary
Nearly half of the world's population is at risk of malaria, a disease caused by the protozoan parasite Plasmodium, which is estimated to cause more than 240,000,000 infections and kill more ...than 600,000 people annually. The emergence of Plasmodia resistant to chemoprophylactic treatment highlights the urgency to develop more effective vaccines. In this regard, whole sporozoite vaccination approaches in murine models and human challenge studies have provided substantial insight into the immune correlates of protection from malaria. From these studies, CD8+ T cells have come to the forefront, being identified as critical for vaccine‐mediated liver‐stage immunity that can prevent the establishment of the symptomatic blood stages and subsequent transmission of infection. However, the unique biological characteristics required for CD8+ T cell protection from liver‐stage malaria dictate that more work must be done to design effective vaccines. In this review, we will highlight a subset of studies that reveal basic aspects of memory CD8+ T cell‐mediated protection from liver‐stage malaria infection.
T cell-mediated immunity to malaria Kurup, Samarchith P; Butler, Noah S; Harty, John T
Nature reviews. Immunology,
07/2019, Letnik:
19, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Immunity to malaria has been linked to the availability and function of helper CD4
T cells, cytotoxic CD8
T cells and γδ T cells that can respond to both the asymptomatic liver stage and the ...symptomatic blood stage of Plasmodium sp. infection. These T cell responses are also thought to be modulated by regulatory T cells. However, the precise mechanisms governing the development and function of Plasmodium-specific T cells and their capacity to form tissue-resident and long-lived memory populations are less well understood. The field has arrived at a point where the push for vaccines that exploit T cell-mediated immunity to malaria has made it imperative to define and reconcile the mechanisms that regulate the development and functions of Plasmodium-specific T cells. Here, we review our current understanding of the mechanisms by which T cell subsets orchestrate host resistance to Plasmodium infection on the basis of observational and mechanistic studies in humans, non-human primates and rodent models. We also examine the potential of new experimental strategies and human infection systems to inform a new generation of approaches to harness T cell responses against malaria.
Historically, the gold-standard benchmark for vaccine immunogenicity has been the induction of neutralizing antibodies detectable in the serum of peripheral blood. However, in recent years there has ...been a new appreciation for the mucosa as an important site for vaccine induced immunity. As a point of first contact, the mucosal tissue represents a major site of immune based detection and restriction of pathogen entry and dissemination. Tissue resident memory T cells (T
rm
) are one of the critical cell types involved in this early detection and restriction of mucosal pathogens. Following tissue-specific infection or vaccination, T
rm
lodge themselves within tissues and can perform rapid sensing and alarm functions to control local re-infections, in an effort that has been defined as important for restriction of a number of respiratory pathogens including influenza and respiratory syncytial virus. Despite this characterized importance, only minor attention has been paid to the importance of T
rm
as a benchmark for vaccine immunogenicity. The purpose of this review is to highlight the functions of T
rm
with particular emphasis on respiratory infections, and to suggest the inclusion of T
rm
elicitation as a benchmark for vaccine immunogenicity in animal models, and where possible, human samples.
CD8+ T cells confer host protection through T-cell-receptor (TCR)-mediated recognition of foreign antigens presented by infected cells. Thus, generation of CD8+ T cell populations with high antigen ...sensitivity is critical for efficient pathogen clearance. Besides selection of high-affinity TCRs, the molecular mechanisms regulating the antigen sensitivity of CD8+ T cells remain poorly defined. Herein, we have demonstrated that the antigen sensitivity of effector and memory CD8+ T cells is dynamically regulated and can be tuned by pathogen-induced inflammatory milieux independently of the selection of cells with higher TCR affinity. Mechanistically, we have demonstrated that the signal-transduction capacity of key TCR proximal molecules is enhanced by inflammatory cytokines, which reduced the antigen density required to trigger antimicrobial functions. Dynamic tuning of CD8+ T cell antigen sensitivity by inflammatory cytokines most likely optimizes immunity to specific pathogens while minimizing the risk of immunopathology at steady state.
► Inflammatory cytokines tune the antigen sensitivity of CD8+ T cells ► Tuning of antigen sensitivity is dynamic and pathogen specific ► Cytokine signaling directly to CD8+ T cells regulates antigen sensitivity ► Inflammatory cytokines enhance TCR signaling of effector and memory CD8+ T cells
Infection or vaccination confers heightened resistance to pathogen rechallenge because of quantitative and qualitative differences between naive and primary memory T cells. Herein, we show that ...secondary (boosted) memory CD8
+ T cells were better than primary memory CD8
+ T cells in controlling some, but not all acute infections with diverse pathogens. However, secondary memory CD8
+ T cells were less efficient than an equal number of primary memory cells at preventing chronic LCMV infection and are more susceptible to functional exhaustion. Importantly, localization of memory CD8
+ T cells within lymph nodes, which is reduced by antigen restimulation, was critical for both viral control in lymph nodes and for the sustained CD8
+ T cell response required to prevent chronic LCMV infection. Thus, repeated antigen stimulation shapes memory CD8
+ T cell populations to either enhance or decrease per cell protective immunity in a pathogen-specific manner, a concept of importance in vaccine design against specific diseases.
► Secondary (boosted) memory CD8
+ T cells protect better against some acute infections ► Secondary memory CD8
+ T cells are more “exhaustible” than primary memory cells ► Primary memory CD8
+ T cells are better at preventing chronic LCMV infection ► Lymph node entry is critical for memory CD8
+ T cell protection against chronic LCMV
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. Unexpectedly, RSV infection of mice with pre-existing CD8 T cell memory led to exacerbated weight loss, pulmonary disease, and lethal immunopathology. The exacerbated disease in immunized mice was not epitope-dependent and occurred despite a significant reduction in RSV viral titers. In addition, the lethal immunopathology was unique to the context of an RSV infection as mice were protected from a normally lethal challenge with a recombinant influenza virus expressing an RSV epitope. Memory CD8 T cells rapidly produced IFN-γ following RSV infection resulting in elevated protein levels in the lung and periphery. Neutralization of IFN-γ in the respiratory tract reduced morbidity and prevented mortality. These results demonstrate that in contrast to other respiratory viruses, RSV-specific memory CD8 T cells can induce lethal immunopathology despite mediating enhanced viral clearance.
Lung-resident primary memory CD8+ T cell populations (Trm) induced by a single influenza infection decline within months, rendering the host susceptible to new heterosubtypic influenza infections. ...Here, we demonstrate that, relative to single virus exposure, repeated antigen exposure dramatically alters the dynamics of influenza-specific lung Trm populations. Lung Trm derived from repeatedly stimulated circulating memory CD8+ T cells exhibit extended durability and protective heterosubtypic immunity relative to primary lung Trm. Parabiosis studies reveal that the enhanced durability of lung Trm after multiple antigen encounters resulted from the generation of long-lasting circulating effector memory (Tem) populations, which maintained the ability to be recruited to the lung parenchyma and converted to Trm, in combination with enhanced survival of these cells in the lung. Thus, generating a long-lasting Trm precursor pool through repeated intranasal immunizations might be a promising strategy to establish long-lasting lung Trm-mediated heterosubtypic immunity against influenza.
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•Influenza-specific quaternary (4°M) lung Trm persist longer than 1°M Trm•Circulating 4°M CD8+ T cells have prolonged Tem phenotype compared to 1°M CD8+ T cells•Circulating 4°M Tem exhibit sustained migration to the lung and conversion to Trm•Prolonged lung 4°M Trm maintenance extends heterosubtypic immunity to influenza
Van Braeckel-Budimir et al. find that repeated antigen exposure by influenza virus infection in the lung enhances the durability of lung CD8+ T resident memory populations and extends the duration of heterosubtypic immunity against influenza virus.
Infection of erythrocytes with Plasmodium species induces clinical malaria. Parasite-specific CD4(+) T cells correlate with lower parasite burdens and severity of human malaria and are needed to ...control blood-stage infection in mice. However, the characteristics of CD4(+) T cells that determine protection or parasite persistence remain unknown. Here we show that infection of humans with Plasmodium falciparum resulted in higher expression of the inhibitory receptor PD-1 associated with T cell dysfunction. In vivo blockade of the PD-1 ligand PD-L1 and the inhibitory receptor LAG-3 restored CD4(+) T cell function, amplified the number of follicular helper T cells and germinal-center B cells and plasmablasts, enhanced protective antibodies and rapidly cleared blood-stage malaria in mice. Thus, chronic malaria drives specific T cell dysfunction, and proper function can be restored by inhibitory therapies to enhance parasite control.
Shaping and reshaping CD8 + T-cell memory Harty, John T; Badovinac, Vladimir P
Nature reviews. Immunology,
200802, 2008-Feb, 2008-02-00, 20080201, Letnik:
8, Številka:
2
Journal Article
Recenzirano
Odprti dostop
The ability to develop and sustain populations of memory T cells after infection or immunization is a hallmark of the adaptive immune response and a basis for protective vaccination against ...infectious disease. Technical advances that allow direct ex vivo identification and characterization of antigen-specific CD8+ T cells at various stages of the response to infection or vaccination in mouse models have fuelled efforts to characterize the factors that control memory CD8+ T-cell generation. Here, we dissect the input signals that shape the characteristics of the memory CD8+ T-cell response and discuss how manipulation of these signals has the potential to reshape CD8+ T-cell memory and improve the efficacy of vaccination.
Radiation-attenuated Plasmodium sporozoites (RAS) are the only vaccine shown to induce sterilizing protection against malaria in both humans and rodents. Importantly, these "whole-parasite" vaccines ...are currently under evaluation in human clinical trials. Studies with inbred mice reveal that RAS-induced CD8 T cells targeting liver-stage parasites are critical for protection. However, the paucity of defined T cell epitopes for these parasites has precluded precise understanding of the specific characteristics of RAS-induced protective CD8 T cell responses. Thus, it is not known whether quantitative or qualitative differences in RAS-induced CD8 T cell responses underlie the relative resistance or susceptibility of immune inbred mice to sporozoite challenge. Moreover, whether extraordinarily large CD8 T cell responses are generated and required for protection following RAS immunization, as has been described for CD8 T cell responses following single-antigen subunit vaccination, remains unknown. Here, we used surrogate T cell activation markers to identify and track whole-parasite, RAS-vaccine-induced effector and memory CD8 T cell responses. Our data show that the differential susceptibility of RAS-immune inbred mouse strains to Plasmodium berghei or P. yoelii sporozoite challenge does not result from host- or parasite-specific decreases in the CD8 T cell response. Moreover, the surrogate activation marker approach allowed us for the first time to evaluate CD8 T cell responses and protective immunity following RAS-immunization in outbred hosts. Importantly, we show that compared to a protective subunit vaccine that elicits a CD8 T cell response to a single epitope, diversifying the targeted antigens through whole-parasite RAS immunization only minimally, if at all, reduced the numerical requirements for memory CD8 T cell-mediated protection. Thus, our studies reveal that extremely high frequencies of RAS-induced memory CD8 T cells are required, but may not suffice, for sterilizing anti-Plasmodial immunity. These data provide new insights into protective CD8 T cell responses elicited by RAS-immunization in genetically diverse hosts, information with relevance to developing attenuated whole-parasite vaccines.
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