CD8 T cell memory development: CD4 T cell help is appreciated

Khanolkar, Aaruni; Badovinac, Vladimir P.; Harty, John T.

doi:10.1007/s12026-007-0081-4

Cited by 60 publications

(67 citation statements)

References 65 publications

(87 reference statements)

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“…In contrast, many pathogenic infections, such as influenza, lymphocytic choriomeningitis virus (LCMV), vesicular stomatitis virus, or other pathogens, induce strong primary CD8 + T cell responses in the absence of CD4 + T cell help (4)(5)(6). The ability of these infectious agents to directly activate APCs via pattern recognition receptors is thought to circumvent the need for CD4 + T cell help (7,8).…”

Section: T Is Widely Accepted That Certain Cd8mentioning

confidence: 99%

Th Cells Act Via Two Synergistic Pathways To Promote Antiviral CD8+ T Cell Responses

Wiesel

Joller

Ehlert

et al. 2010

The Journal of Immunology

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Section: T Is Widely Accepted That Certain Cd8mentioning

confidence: 99%

Th Cells Act Via Two Synergistic Pathways To Promote Antiviral CD8+ T Cell Responses

Wiesel

Joller

Ehlert

et al. 2010

The Journal of Immunology

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“…It has been well established that CD4 ϩ T cells provide critical help for inducing long-lived protective antibody production by B cells (8) and for generating effective CD8 ϩ memory T cells (9). Thus, it is believed that the effects of adjuvants on enhancing antibody responses to T cell-dependent vaccine antigens are mediated by CD4…”

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confidence: 99%

Effects of MF59 Adjuvant on Induction of Isotype-Switched IgG Antibodies and Protection after Immunization with T-Dependent Influenza Virus Vaccine in the Absence of CD4 ⁺ T Cells

Lee

Kim

et al. 2016

J Virol

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CD4؉ T cells play a central role in orchestrating adaptive immunity. To better understand the roles of CD4 ؉ T cells in the effects of adjuvants, we investigated the efficacy of a T-dependent influenza virus split vaccine with MF59 or alum in CD4 knockout (CD4KO) and wild-type (WT) mice. CD4 ؉ T cells were required for the induction of IgG antibody responses to the split vaccine and the effects of alum adjuvant. In contrast, MF59 was found to be highly effective in raising isotype-switched IgG antibodies to a T-dependent influenza virus split vaccine in CD4KO mice or CD4-depleted WT mice equivalent to those in intact WT mice, thus overcoming the deficiency of CD4 ؉ T cells in helping B cells and inducing immunity against influenza virus. Vaccination with the MF59-adjuvanted influenza virus vaccine was able to induce protective CD8 ؉ T cells and long-lived antibody-secreting cells in CD4KO mice. The effects of MF59 adjuvant in CD4KO mice might be associated with uric acid, inflammatory cytokines, and the recruitment of multiple immune cells at the injection site, but their cellularity and phenotypes were different from those in WT mice. These findings suggest a new paradigm of CD4-independent adjuvant mechanisms, providing the rationales to improve vaccine efficacy in infants, the elderly, immunocompromised patients, as well as healthy adults. IMPORTANCE MF59-adjuvanted influenza vaccines were licensed for human vaccination, but the detailed mechanisms are not fully elucidated. CD4 ؉ T cells are required to induce antibody isotype switching and long-term memory responses. In contrast, we discovered that MF59 was highly effective in inducing isotype-switched IgG antibodies and long-term protective immune responses to a T-dependent influenza vaccine independent of CD4؉ T cells. These findings are highly significant for the following reasons: (i) MF59 can overcome a defect of CD4 ؉ T cells in inducing protective immunity to vaccination with a T-dependent influenza virus vaccine; (ii) a CD4-independent pathway can be an alternative mechanism for certain adjuvants such as MF59; and (iii) this study has significant implications for improving vaccine efficacies in young children, the elderly, and immunocompromised populations. Vaccination is used to induce protective antibodies and immune memory to prevent against future pathogens. Adjuvants can play a key role in the development of successful vaccines by enhancing immunogenicity and leading to antigen dose-sparing effects, fewer immunizations, and long-lasting B and T cell immunity. Aluminum hydroxide (alum) has been the most common adjuvant used in human vaccines for Ͼ70 years. Alum may act via various mechanisms such as antigen depot, benign cell death (1), and recruitment of neutrophils and macrophages partially through inflammasome signaling pathways (2, 3). An inflammasome pathway of alum adjuvant effects is controversial due to the lack of evidence in vivo (4, 5). MF59 is an oil-in-water emulsion adjuvant licensed in 1997 and has been used in influenza v...

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“…Most importantly, CD40/CD40L pathway has also been shown to provide the molecular basis for the central role played by "helper" CD4 + T cells during the priming of naïve CD8 + T cells in promoting their differentiation in long-lasting memory cells [17]. In particular, CD40L expressed by activated CD4 + T cells triggers CD40 receptor on DC, thereby enhancing their antigen presentation capacity due to the upregulation of MHC class I/II, costimulatory molecules, and increased cytokine production [18].Remarkably, generation of memory CD8 + T cells has been shown to be critically dependent on the "help" provided by CD4 + T cells [17,[19][20][21]. Indeed CD8 + T cells induced in "helpless" condition have been reported to be typically characterized by a defective proliferative response due to impaired IL-2 production [19] and/or TRAIL-mediated apoptosis upon secondary stimulation [21].…”

mentioning

confidence: 99%

“…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].An important role in the generation of effective memory CD8 + T cells is played by the conditions of the initial stimulation [35] and CD4 + T-cell help has repeatedly been shown to be of essential relevance [17,19,21]. CD8 + T lymphocytes primed in "helpless" conditions might still be able to kill targets expressing appropriate antigens and MHC, and to produce a limited array of cytokines, but they would fail to respond to specific TCR triggering with proliferation and IL-2 production [19].…”

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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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CD8 T cell memory development: CD4 T cell help is appreciated

Cited by 60 publications

References 65 publications

Th Cells Act Via Two Synergistic Pathways To Promote Antiviral CD8+ T Cell Responses

Th Cells Act Via Two Synergistic Pathways To Promote Antiviral CD8+ T Cell Responses

Effects of MF59 Adjuvant on Induction of Isotype-Switched IgG Antibodies and Protection after Immunization with T-Dependent Influenza Virus Vaccine in the Absence of CD4 ⁺ T Cells

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

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CD8 T cell memory development: CD4 T cell help is appreciated

Cited by 60 publications

References 65 publications

Th Cells Act Via Two Synergistic Pathways To Promote Antiviral CD8+ T Cell Responses

Th Cells Act Via Two Synergistic Pathways To Promote Antiviral CD8+ T Cell Responses

Effects of MF59 Adjuvant on Induction of Isotype-Switched IgG Antibodies and Protection after Immunization with T-Dependent Influenza Virus Vaccine in the Absence of CD4 + T Cells

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

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Effects of MF59 Adjuvant on Induction of Isotype-Switched IgG Antibodies and Protection after Immunization with T-Dependent Influenza Virus Vaccine in the Absence of CD4 ⁺ T Cells

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