Protective Capacity of Memory CD8+ T Cells Is Dictated by Antigen Exposure History and Nature of the Infection

Nolz, Jeffrey C.; Harty, John T.

doi:10.1016/j.immuni.2011.03.020

Cited by 109 publications

(154 citation statements)

References 44 publications

(66 reference statements)

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“…These lymphocytes are characterized by a high proliferative potential in response to stimulation by nonprofessional APCs, leading to 4-5 cell divisions in a large majority of cells. In addition, advanced differentiation toward effector T cells was also detectable [10]. Further research is warranted to clarify whether the latter effect results from asymmetric division of memory T cells [3].…”

Section: Discussionmentioning

confidence: 95%

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CD40 ligand‐expressing recombinant vaccinia virus promotes the generation of CD8⁺ central memory T cells

et al. 2015

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Central memory CD8 + T cells (T CM ) play key roles in the protective immunity against infectious agents, cancer immunotherapy, and adoptive treatments of malignant and viral diseases. CD8+ T CM cells are characterized by specific phenotypes, homing, and proliferative capacities. However, CD8 + T CM -cell generation is challenging, and usually requires CD4 + CD40L + T-cell "help" during the priming of naïve CD8 + T cells. We have generated a replication incompetent CD40 ligand-expressing recombinant vaccinia virus (rVV40L) to promote the differentiation of human naïve CD8 + T cells into T CM specific for viral and tumor-associated antigens. Soluble CD40 ligand recombinant protein (sCD40L), and vaccinia virus wild-type (VV WT), alone or in combination, were used as controls. Here, we show that, in the absence of CD4 + T cells, a single "in vitro" stimulation of naïve CD8 + T cells by rVV40L-infected nonprofessional CD14 + antigen presenting cells promotes the rapid generation of viral or tumor associated antigen-specific CD8 + T cells displaying T CM phenotypic and functional properties. These observations demonstrate the high ability of rVV40L to fine tune CD8 + mediated immune responses, and strongly support the use of similar reagents for clinical immunization and adoptive immunotherapy purposes.Keywords: Antigen presenting cells r Central memory T cells r CD40-CD40L r CD4 + T cells r CD8 + T cells r Immunological memory r Vaccinia virus Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionGeneration of immunological memory represents a key tenet of the adaptive immune system. Memory T cells display the exquisite Correspondence: Dr. Paul Zajac e-mail: paul.zajac@usb.ch ability to respond to previously experienced antigens with clonal expansion and with the rapid elicitation of multiple effector function [1]. However, the origin of memory CD8 + T cells is still debated, particularly concerning the relationship between effector and memory cells [2].Current understanding is consistent with the "one cell, multiple fates" model postulating that memory and effector T cells C 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2016. 46: 420-431 Immunomodulation 421 may arise from single naïve CD8 + T-cell precursor undergoing asymmetric division originating two daughter cells with different cell fates [3]. Alternatively, a linear differentiation model proposes that memory CD8 + T lymphocytes may derive from effector cells surviving the contraction phase of the primary immune response [4]. Memory compartment encompasses lymphocyte subpopulations characterized by different phenotypes, functional properties, and anatomic locations. Two main subsets, central (T CM ) and effector memory (T EM ) lymphocytes, displaying a differential expression of homing and chemokine receptors have consistently been identified [5,6].Notably, T CM are characterized by high proliferative potential in response to antigen stimulation and...

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Section: Discussionmentioning

confidence: 95%

“…Furthermore, transfer of "in vitro" induced antigen-specific CD8 + T CM warrants a high effectiveness of adoptive immunotherapy treatments against cancer or virus infections [9,10,32,33]. Thus, the induction of T CM cells represents a key clinical priority [34].…”

Section: Discussionmentioning

confidence: 99%

CD40 ligand‐expressing recombinant vaccinia virus promotes the generation of CD8⁺ central memory T cells

et al. 2015

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“…Although many of these newly formed daughter cells are short-lived, a substantial percentage will survive the contraction phase and persist for long periods of time as memory cells, capable of providing protection from pathogen reinfection (3)(4)(5). In fact, memory CD8 + T cell populations are able to confer host protection against infection in a number of different experimental models (6)(7)(8)(9).…”

Section: Introductionmentioning

confidence: 99%

“…L-selectin is expressed by many leukocytes and is critical for lymph node homing of naive CD8 + T cells and a subset of memory CD8 + T cells during the steady state (9,25). In contrast, P-and E-selectin are expressed by inflamed endothelium and assist in the tissue recruitment of leukocytes that express the corresponding ligands (26).…”

Section: Introductionmentioning

confidence: 99%

IL-15 regulates memory CD8+ T cell O-glycan synthesis and affects trafficking

Nolz¹,

Harty²

2014

J. Clin. Invest.

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Memory and naive CD8 + T cells exhibit distinct trafficking patterns. Specifically, memory but not naive CD8 + T cells are recruited to inflamed tissues in an antigen-independent manner. However, the molecular mechanisms that regulate memory CD8 + T cell trafficking are largely unknown. Here, using murine models of infection and T cell transfer, we found that memory but not naive CD8 + T cells dynamically regulate expression of core 2 O-glycans, which interact with P-and E-selectins to modulate trafficking to inflamed tissues. Following infection, antigen-specific effector CD8 + T cells strongly expressed core 2 O-glycans, but this glycosylation pattern was lost by most memory CD8 + T cells. After unrelated infection or inflammatory challenge, memory CD8 + T cells synthesized core 2 O-glycans independently of antigen restimulation. The presence of core 2 O-glycans subsequently directed these cells to inflamed tissue. Memory and naive CD8 + T cells exhibited the opposite pattern of epigenetic modifications at the Gcnt1 locus, which encodes the enzyme that initiates core 2 O-glycan synthesis. The open chromatin configuration in memory CD8 + T cells permitted de novo generation of core 2 O-glycans in a TCR-independent, but IL-15-dependent, manner. Thus, IL-15 stimulation promotes antigen-experienced memory CD8 + T cells to generate core 2 O-glycans, which subsequently localize them to inflamed tissues. These findings suggest that CD8 + memory T cell trafficking potentially can be manipulated to improve host defense and immunotherapy.

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“…Administration of harmless antigen would mimic the first infection without causing severe disease, to enable the adaptive immune system to acquire memory about the antigen. In turn, the next time the real pathogen attacks, the adaptive immune system would be able to clear it immediately without the pathogen causing the disease to the vaccinated individual (Murphy et al 2008;Nolz and Harty 2011a). Section 2.3.3 will explain the mechanism of memory acquisition and subsequent selective cytotoxicity of the cellular immunity in more detail.…”

Section: Current Influenza Vaccines and Their Limitationsmentioning

confidence: 99%

Murine polyomavirus VLPs as a platform for cytotoxic T cell epitope-based influenza vaccine candidates

Abidin¹

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This research examined the ability of virus-like particles (VLP) assembled from the coat proteins of Murine polyomavirus (MPyV) to carry cytotoxic T cell (Tc) epitopes. MPyV VLPs can be assembled in vitro from purified subunits composed of pentamers of the major coat protein VP1 called capsomeres; and this approach provides fine control over VLP composition and structure. Tc-epitopes are often highly hydrophobic, which poses a significant bioengineering challenge and two distinct approaches were pursued to determine the optimal delivery strategy of Influenza Tc-epitopes by MPyV VLP. Firstly, identified epitopes were externally presented using established sites for peptide insertion on the MPyV major coat protein, VP1. Secondly, polypeptides possessing multiple epitopes were encapsidated within VP1 VLP using precise elements of the minor coat protein VP2/3 that interact with the interior cavity of capsomeres. Hydrophobicity-related capsomere aggregation arising from single Tc epitope presentation was successfully circumvented by engineering charged amino acids (DD) flanking the epitope displayed on a surface-exposed loop of VP1 and by use of an optimised buffer condition. A multiparametric, high-throughput buffer screen was implemented to optimise pH and buffer additives during affinity tag removal. Stable modified capsomere recovered from this reaction were assembly competent in the presence of L-Arginine, and VLP yield was high when modular capsomeres were co-assembled with unmodified VP1 capsomeres forming stable mosaic VLPs. The ability of the MPyV VLP to encapsidate foreign protein was first evaluated and optimised with green fluorescent protein (GFP) as a model protein to enable monitoring and analysis.A minimal VP1-interacting sequence was defined from the carboxy-terminus of VP2/3 (VP2C) and fused to the amino-terminus of GFP, ensuring internalisation of the reporter protein. VP1:VP2C-GFP capsomere complexes were successfully recovered when VP1 was co-expressed with VP2C-GFP, whereas complex formation was not observed when VP1 and VP2C-GFP were mixed in vitro.Recovered capsomere complexes were assembly competent and amount of encapsidated GFP was controllable when VP1:VP2C-GFP capsomere complexes were co-assembled with unmodified VP1 capsomeres in a defined molar ratio. The encapsidation approach was then applied to a subdomain of the Influenza matrix protein M1 by co-expressing VP1 with VP2C-M1-I. M1-I capsomere complexes were assembly competent as indicated by gel electrophoresis, dynamic light scattering, and transmission electron microscopy. To enable recovery of VLPs for analysis and characterisation as well as to confirm encapsidation and the formation of mosaic VLPs, a semi-preparative size exclusion chromatography method was developed. This research was able to address bioengineering challenges posed by hydrophobic epitope presentation and developed MPyV

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Protective Capacity of Memory CD8+ T Cells Is Dictated by Antigen Exposure History and Nature of the Infection

Cited by 109 publications

References 44 publications

CD40 ligand‐expressing recombinant vaccinia virus promotes the generation of CD8⁺ central memory T cells

CD40 ligand‐expressing recombinant vaccinia virus promotes the generation of CD8⁺ central memory T cells

IL-15 regulates memory CD8+ T cell O-glycan synthesis and affects trafficking

Murine polyomavirus VLPs as a platform for cytotoxic T cell epitope-based influenza vaccine candidates

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Protective Capacity of Memory CD8+ T Cells Is Dictated by Antigen Exposure History and Nature of the Infection

Cited by 109 publications

References 44 publications

CD40 ligand‐expressing recombinant vaccinia virus promotes the generation of CD8+ central memory T cells

CD40 ligand‐expressing recombinant vaccinia virus promotes the generation of CD8+ central memory T cells

IL-15 regulates memory CD8+ T cell O-glycan synthesis and affects trafficking

Murine polyomavirus VLPs as a platform for cytotoxic T cell epitope-based influenza vaccine candidates

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Product

Resources

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CD40 ligand‐expressing recombinant vaccinia virus promotes the generation of CD8⁺ central memory T cells

CD40 ligand‐expressing recombinant vaccinia virus promotes the generation of CD8⁺ central memory T cells