Protracted Protection to <i>Plasmodium berghei</i> Malaria Is Linked to Functionally and Phenotypically Heterogeneous Liver Memory CD8+ T Cells

Berenzon, Dmitri; Schwenk, Robert; Letellier, Lisa; Guebre‐Xabier, Mimi; Williams, Jon H Sims; Krzych, Urszula

doi:10.4049/jimmunol.171.4.2024

Cited by 107 publications

(202 citation statements)

References 48 publications

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“…Th1-type responses also control Leishmania major but Th2-type responses exacerbate the disease [27]. This is consistent with our observation [7] that IFN-c-producing liver CD8 T cells increase between 1 and 6 h after challenge of cspz-immune mice. Effector CD8 T cells also might require costimulation by CD40 and/or CD80, which increased on c-spz-immune KC after challenge; moreover, they might rely on activated CD4 T cells, thus it is relevant that class II molecules on KC increased, albeit insignificantly, after challenge of c-spz-immune mice.…”

Section: Discussionsupporting

confidence: 91%

“…MHC class I and inflammatory cytokines are sine qua non for the activation of Ag-specific effector CD8 T cells, which are not detected in spz-challenged naive mice [7]. Spz may have interacted directly or indirectly with KC.…”

Section: Discussionmentioning

confidence: 98%

“…IHMC were isolated from livers [7] and incubated with anti-CD8 and -CD4-conjugated magnetic beads, washed and then applied to a MS magnetic column. The flow through cells were labeled with biotinylated anti-Mac3 Ab (Cederlane, Ontario, Canada) and anti-biotin beads (Miltenyi Biotec), and applied to a second MS column.…”

Section: Preparation Of Kcmentioning

confidence: 99%

“…Protection is multi-factorial involving both innate and acquired immune responses [5]. We demonstrated that protection induced in C57BL/6 mice with P. berghei cspz is maintained by MHC class I-dependent [6], IFN-cproducing liver memory CD8 T cells [7]. There is a paucity of information, however, regarding the role of APC in the induction and maintenance of cells conferring protection and specifically the role of Kupffer cells (KC) remains unexplored.…”

Section: Introductionmentioning

confidence: 99%

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The immune status of Kupffer cells profoundly influences their responses to infectiousPlasmodium berghei sporozoites

Steers

Schwenk

Bacon³

et al. 2005

Eur. J. Immunol.

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Multi-factorial immune mechanisms underlie protection induced with radiationattenuated Plasmodia sporozoites (c-spz). Spz pass through Kupffer cells (KC) before invading hepatocytes but the involvement of KC in protection is poorly understood. In this study we investigated whether c-spz-immune KC respond to infectious spz in a manner that is distinct from the response of naive KC to infectious spz. KC were isolated from (1) naive, (2) spz-infected, (3) c-spz-immune, and (4) c-spz-immune-challenged C57BL/6 mice and examined for the expression of MHC class I and II, CD40 and CD80/CD86, IL-10 and IL-12 responses and antigen-presenting cell (APC) function. KC from c-spz-immune-challenged mice up-regulated class I and costimulatory molecules and produced elevated IL-12p40, relative to naive KC. In contrast, KC from naive mice exposed to infectious spz down-modulated class I and IL-12p40 was undetectable. Accordingly, KC from spz-infected mice had reduced APC function, while KC from c-spz-immune-challenged mice exhibited augmented APC activity. The nearly opposite responses are consistent with the fact that spz challenge of c-spz-immune mice results in long-lasting sterile protection, while infection of naive mice always results in malaria.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 98%

Section: Preparation Of Kcmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The immune status of Kupffer cells profoundly influences their responses to infectiousPlasmodium berghei sporozoites

Steers

Schwenk

Bacon³

et al. 2005

Eur. J. Immunol.

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“…Naive T cell expansion and conversion into conventional memory T cells, as well as central (proliferation) and effector (IFN-c secretion) memory T cell effector functions were also affected. In liver-stage malaria, protective immunity can be associated with specific central or effector memory T cell subpopulations [17,18]. The existence and selection of these novel multi-level (naive, memory-central and memory-effector) antagonistic T cell epitopes within MSP-1 therefore offers an unusual and powerful immune evasion strategy for the malaria parasite.…”

Section: Introductionmentioning

confidence: 99%

Dimorphic Plasmodium falciparum merozoite surface protein‐1 epitopes turn off memory T cells and interfere with T cell priming

et al. 2006

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The leading blood-stage malaria vaccine candidate antigen, Plasmodium falciparum merozoite surface protein-1 (MSP-1) occurs in two major allelic types worldwide. The molecular basis promoting this stable dimorphism is unknown. In this study, we have shown that allelic altered peptide ligand (APL) T cell epitopes of MSP-1 mutually inhibited IFN-c secretion as well as proliferation of CD4 + T cells in 27/34 malaria exposed Gambian volunteers. Besides this inhibition of malaria-specific immunity, the same variant epitopes were also able to impair the priming of human T cells in malaria naive individuals. Epitope variants capable of interfering with T cell priming as well as inhibiting memory T cell effector functions offer a uniquely potent combination for immune evasion. Indeed, enhanced co-habitation of parasites bearing such antagonistic allelic epitope regions was observed in a study of 321 West African children, indicating a survival advantage for parasites able to engage this inhibitory immune interference mechanism.

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TAP‐mediated processing of exoerythrocytic antigens is essential for protection induced with radiation‐attenuated Plasmodium sporozoites

et al. 2016

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MHC class I dependent CD8 + T cells are essential for protection induced by radiationattenuated Plasmodium sporozoites (RAS) in murine malaria models. Apart from the mechanism of activation of CD8 + T cells specific for the circumsporozoite protein, the major sporozoite antigen (Ag), CD8 + T cells specific for other exoerythrocytic Ags that have been shown to mediate protection have not been thoroughly investigated. Specifically, mechanisms of processing and presentation of exoerythrocytic Ags, which includes liver stage (LS) Ags, remain poorly understood. We hypothesize that as exogenous proteins, LS Ags are processed by mechanisms involving either the TAP-dependent phagosomalto-cytosol or TAP-independent vacuolar pathway of cross-presentation. We used TAPdeficient mice to investigate whether LS Ag mediated induction of naïve CD8 + T cells and their recall during sporozoite challenge occur by the TAP-dependent or TAP-independent pathways. On the basis of functional attributes, CD8 + T cells were activated via the TAPindependent pathway during immunizations with Plasmodium berghei RAS; however, IFN-γ + CD8 + T cells previously induced by P. berghei RAS in TAP-deficient mice failed to be recalled against sporozoite challenge and the mice became parasitemic. On the basis of these observations, we propose that TAP-associated Ag processing is indispensable for sterile protection induced with P. berghei RAS.Keywords: Antigen presenting cells · CD8 + T cells · Liver · Plasmodium · Transporter associated with antigen processing (TAP) Additional supporting information may be found in the online version of this article at the publisher's web-site Introduction CD8 + T cells provide a critical network of responses that underlie lasting protective immunity against viral, microbial, and parasitic infections [1]. A subset of antigen (Ag) induced CD8 + T cells acquire an effector (E) function and these CD8 + effector T (T E ) cells become poised to eliminate pathogen infected cells, Correspondence: Dr. Urszula Krzych e-mail: Urszula.Krzych1.civ@mail.mil a process that is typically MHC I dependent. The induction of Ag-specific CD8 + T cells requires ligation of the TCR by MHC I:peptide complexes that are formed during Ag processing and displayed on APCs, followed by the provision of secondary and tertiary signals, such as costimulatory molecules and cytokines, respectively [2,3]. Several distinct mechanisms of Ag processing have been described for the MHC I pathway and the utilization of a particular pathway depends in part on the Ag itself. For example, most endogenous Ags, such as viral proteins synthesized within the cytosol of infected host cells, are processed along the classical pathway involving proteosomal degradation followed by Published 2015. This article is a U.S. Government work and is in the public domain in the USA www.eji-journal.eu 886Alexander Pichugin et al. Eur. J. Immunol. 2016. 46: 885-896 TAP-dependent transfer of oligopeptides into the ER. Subsequent trimming by ER aminopeptidase associated with A...

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Protracted Protection to Plasmodium berghei Malaria Is Linked to Functionally and Phenotypically Heterogeneous Liver Memory CD8+ T Cells

Cited by 107 publications

References 48 publications

The immune status of Kupffer cells profoundly influences their responses to infectiousPlasmodium berghei sporozoites

The immune status of Kupffer cells profoundly influences their responses to infectiousPlasmodium berghei sporozoites

Dimorphic Plasmodium falciparum merozoite surface protein‐1 epitopes turn off memory T cells and interfere with T cell priming

TAP‐mediated processing of exoerythrocytic antigens is essential for protection induced with radiation‐attenuated Plasmodium sporozoites

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