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Journal ArticleDOI

T-cell quality in memory and protection: implications for vaccine design

01 Apr 2008-Nature Reviews Immunology (Nature Publishing Group)-Vol. 8, Iss: 4, pp 247-258
TL;DR: The importance of using multiparameter flow cytometry to better understand the functional capacity of effector and memory T-cell responses, thereby enabling the development of preventative and therapeutic vaccine strategies for infections is highlighted.
Abstract: T cells mediate effector functions through a variety of mechanisms. Recently, multiparameter flow cytometry has allowed a simultaneous assessment of the phenotype and multiple effector functions of single T cells; the delineation of T cells into distinct functional populations defines the quality of the response. New evidence suggests that the quality of T-cell responses is crucial for determining the disease outcome to various infections. This Review highlights the importance of using multiparameter flow cytometry to better understand the functional capacity of effector and memory T-cell responses, thereby enabling the development of preventative and therapeutic vaccine strategies for infections.
Citations
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Journal ArticleDOI
TL;DR: This ALVAC-HIV and AIDSVAX B/E vaccine regimen may reduce the risk of HIV infection in a community-based population with largely heterosexual risk and offer insight for future research.
Abstract: In the intention-to-treat analysis involving 16,402 subjects, there was a trend toward the prevention of HIV-1 infection among the vaccine recipients, with a vaccine efficacy of 26.4% (95% confidence interval [CI], −4.0 to 47.9; P = 0.08). In the perprotocol analysis involving 12,542 subjects, the vaccine efficacy was 26.2% (95% CI, −13.3 to 51.9; P = 0.16). In the modified intention-to-treat analysis involving 16,395 subjects (with the exclusion of 7 subjects who were found to have had HIV-1 infection at baseline), the vaccine efficacy was 31.2% (95% CI, 1.1 to 52.1; P = 0.04). Vaccination did not affect the degree of viremia or the CD4+ T-cell count in subjects in whom HIV-1 infection was subsequently diagnosed. Conclusions This ALVAC-HIV and AIDSVAX B/E vaccine regimen may reduce the risk of HIV infection in a community-based population with largely heterosexual risk. Vaccination did not affect the viral load or CD4+ count in subjects with HIV infection. Although the results show only a modest benefit, they offer insight for future research. (ClinicalTrials.gov number, NCT00223080.)

2,960 citations

Journal ArticleDOI
02 Jul 2009-Nature
TL;DR: It is shown that mTOR (mammalian target of rapamycin, also known as FRAP1) is a major regulator of memory CD8 T-cell differentiation, and in contrast to what was expected, the immunosuppressive drug Rapamycin has immunostimulatory effects on the generation of memoryCD8 T cells.
Abstract: Memory CD8 T cells are a critical component of protective immunity, and inducing effective memory T-cell responses is a major goal of vaccines against chronic infections and tumours. Considerable effort has gone into designing vaccine regimens that will increase the magnitude of the memory response, but there has been minimal emphasis on developing strategies to improve the functional qualities of memory T cells. Here we show that mTOR (mammalian target of rapamycin, also known as FRAP1) is a major regulator of memory CD8 T-cell differentiation, and in contrast to what we expected, the immunosuppressive drug rapamycin has immunostimulatory effects on the generation of memory CD8 T cells. Treatment of mice with rapamycin following acute lymphocytic choriomeningitis virus infection enhanced not only the quantity but also the quality of virus-specific CD8 T cells. Similar effects were seen after immunization of mice with a vaccine based on non-replicating virus-like particles. In addition, rapamycin treatment also enhanced memory T-cell responses in non-human primates following vaccination with modified vaccinia virus Ankara. Rapamycin was effective during both the expansion and contraction phases of the T-cell response; during the expansion phase it increased the number of memory precursors, and during the contraction phase (effector to memory transition) it accelerated the memory T-cell differentiation program. Experiments using RNA interference to inhibit expression of mTOR, raptor (also known as 4932417H02Rik) or FKBP12 (also known as FKBP1A) in antigen-specific CD8 T cells showed that mTOR acts intrinsically through the mTORC1 (mTOR complex 1) pathway to regulate memory T-cell differentiation. Thus these studies identify a molecular pathway regulating memory formation and provide an effective strategy for improving the functional qualities of vaccine- or infection-induced memory T cells.

1,384 citations

Journal ArticleDOI
TL;DR: The differentiation of T cells producing only IL-22 was efficiently induced in naive T cells by plasmacytoid dendritic cells in an IL-6- and tumor necrosis factor–dependent way and delineate a previously unknown subset of human CD4+ effector T cells dedicated to skin pathophysiology.
Abstract: Helper T cells become polarized to effect a 'division of labor'. Sallusto and Spits and colleagues identify a new subset of skin-homing helper T cells, TH-22 cells, that secrete interleukin 22.

1,043 citations


Cites methods from "T-cell quality in memory and protec..."

  • ...We then stimulated the four T cell subsets and expanded them in vitro for 7 d; we then measured production of IL-22, IL-17 and IFN-γ by multicolor intracellular staining and analyzed the data with Boolean gatin...

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Journal ArticleDOI
TL;DR: Algorithms and a graphical interface originally developed to support the analysis of T cell functional profiles are reported on and a statistic for the nonparametric comparison of complex distributions to test for difference between groups of samples based on multi‐component measurements is defined.
Abstract: Polychromatic flow cytometry results in complex, multivariate datasets. To date, tools for the aggregate analysis of these datasets across multiple specimens grouped by different categorical variables, such as demographic information, have not been optimized. Often, the exploration of such datasets is accomplished by visualization of patterns with pie charts or bar charts, without easy access to statistical comparisons of measurements that comprise multiple components. Here we report on algorithms and a graphical interface we developed for these purposes. In particular, we discuss thresholding necessary for accurate representation of data in pie charts, the implications for display and comparison of normalized versus unnormalized data, and the effects of averaging when samples with significant background noise are present. Finally, we define a statistic for the nonparametric comparison of complex distributions to test for difference between groups of samples based on multi-component measurements. While originally developed to support the analysis of T cell functional profiles, these techniques are amenable to a broad range of datatypes.

743 citations


Cites background or methods from "T-cell quality in memory and protec..."

  • ...For analysis of cytokine responses, we refer to the normalized distribution as the ‘‘quality’’ of the response (8)....

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  • ...There is evidence that the pattern of production of these cytokines, termed ‘‘quality’’ (8), rather than the magnitude of the response, may be an important correlate of protection against pathogens (9–13)....

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Journal ArticleDOI
TL;DR: Consistent with previous trials, the MRKAd5 HIV-1 gag/pol/nef vaccine was highly immunogenic for inducing HIV-specific CD8+ T cells and suggest that future candidate vaccines have to elicit responses that either exceed in magnitude or differ in breadth or function from those recorded in this trial.

719 citations

References
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Journal Article
TL;DR: A panel of antigen-specific mouse helper T cell clones was characterized according to patterns of lymphokine activity production, and two types of T cell were distinguished.
Abstract: A panel of antigen-specific mouse helper T cell clones was characterized according to patterns of lymphokine activity production, and two types of T cell were distinguished. Type 1 T helper cells (TH1) produced IL 2, interferon-gamma, GM-CSF, and IL 3 in response to antigen + presenting cells or to Con A, whereas type 2 helper T cells (TH2) produced IL 3, BSF1, and two other activities unique to the TH2 subset, a mast cell growth factor distinct from IL 3 and a T cell growth factor distinct from IL 2. Clones representing each type of T cell were characterized, and the pattern of lymphokine activities was consistent within each set. The secreted proteins induced by Con A were analyzed by biosynthetic labeling and SDS gel electrophoresis, and significant differences were seen between the two groups of T cell line. Both types of T cell grew in response to alternating cycles of antigen stimulation, followed by growth in IL 2-containing medium. Examples of both types of T cell were also specific for or restricted by the I region of the MHC, and the surface marker phenotype of the majority of both types was Ly-1+, Lyt-2-, L3T4+, Both types of helper T cell could provide help for B cells, but the nature of the help differed. TH1 cells were found among examples of T cell clones specific for chicken RBC and mouse alloantigens. TH2 cells were found among clones specific for mouse alloantigens, fowl gamma-globulin, and KLH. The relationship between these two types of T cells and previously described subsets of T helper cells is discussed.

7,567 citations

Journal ArticleDOI
14 Oct 1999-Nature
TL;DR: It is shown that expression of CCR7, a chemokine receptor that controls homing to secondary lymphoid organs, divides human memory T cells into two functionally distinct subsets, which are named central memory (TCM) and effector memory (TEM).
Abstract: Naive T lymphocytes travel to T-cell areas of secondary lymphoid organs in search of antigen presented by dendritic cells. Once activated, they proliferate vigorously, generating effector cells that can migrate to B-cell areas or to inflamed tissues. A fraction of primed T lymphocytes persists as circulating memory cells that can confer protection and give, upon secondary challenge, a qualitatively different and quantitatively enhanced response. The nature of the cells that mediate the different facets of immunological memory remains unresolved. Here we show that expression of CCR7, a chemokine receptor that controls homing to secondary lymphoid organs, divides human memory T cells into two functionally distinct subsets. CCR7- memory cells express receptors for migration to inflamed tissues and display immediate effector function. In contrast, CCR7+ memory cells express lymph-node homing receptors and lack immediate effector function, but efficiently stimulate dendritic cells and differentiate into CCR7- effector cells upon secondary stimulation. The CCR7+ and CCR7- T cells, which we have named central memory (TCM) and effector memory (TEM), differentiate in a step-wise fashion from naive T cells, persist for years after immunization and allow a division of labour in the memory response.

5,537 citations


"T-cell quality in memory and protec..." refers background in this paper

  • ...The paradigm of segregating T cells into 'central memory' T cells (T CM cells) and 'effector memory' T cells (T EM cells), on the basis of their expression of CC-chemokine receptor 7 (CCR7) or CD62L, along with CD45R...

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Journal ArticleDOI
15 Dec 1995-Science
TL;DR: Recombinant human RANTES, Mip-1α, and MIP-1β induced a dose-dependent inhibition of different strains of HIV-1, HIV-2, and simian immunodeficiency virus (SIV) and may have relevance for the prevention and therapy of AIDS.
Abstract: Evidence suggests that CD8 + T lymphocytes are involved in the control of human immunodeficiency virus (HIV) infection in vivo, either by cytolytic mechanisms or by the release of HIV-suppressive factors (HIV-SF). The chemokines RANTES, MIP-1α, and MIP-1β were identified as the major HIV-SF produced by CD8 + T cells. Two active proteins purified from the culture supernatant of an immortalized CD8 + T cell clone revealed sequence identity with human RANTES and MIP-1α. RANTES, MIP-1α, and MIP-1β were released by both immortalized and primary CD8 + T cells. HIV-SF activity produced by these cells was completely blocked by a combination of neutralizing antibodies against RANTES, MIP-1α, and MIP-1β. Recombinant human RANTES, MIP-1α, and MIP-1β induced a dose-dependent inhibition of different strains of HIV-1, HIV-2, and simian immunodeficiency virus (SIV). These data may have relevance for the prevention and therapy of AIDS.

2,894 citations


"T-cell quality in memory and protec..." refers background in this paper

  • ...Also, chemokines such as CC-chemokine ligand 4 (CCL4; previously known as MIP-1β) may act as antagonists to HIV infectio...

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Journal ArticleDOI
TL;DR: Gko mice have been developed which fail to produce IFN-gamma (gko), because of a targeted disruption of the gene for IFNs, and succumb to a rapid and fatal course of tuberculosis that could be delayed, but not prevented, by treatment with exogenous recombinant IFN.
Abstract: Tuberculosis, a major health problem in developing countries, has reemerged in recent years in many industrialized countries. The increased susceptibility of immunocompromised individuals to tuberculosis, and many experimental studies indicate that T cell-mediated immunity plays an important role in resistance. The lymphokine interferon gamma (IFN-gamma) is thought to be a principal mediator of macrophage activation and resistance to intracellular pathogens. Mice have been developed which fail to produce IFN-gamma (gko), because of a targeted disruption of the gene for IFN-gamma. Upon infection with Mycobacterium tuberculosis, although they develop granulomas, gko mice fail to produce reactive nitrogen intermediates and are unable to restrict the growth of the bacilli. In contrast to control mice, gko mice exhibit heightened tissue necrosis and succumb to a rapid and fatal course of tuberculosis that could be delayed, but not prevented, by treatment with exogenous recombinant IFN-gamma.

2,401 citations


"T-cell quality in memory and protec..." refers background in this paper

  • ...In terms of effector function, IFNγ has been shown to have a role in the clearance of various bacterial, parasitic, viral or fungal infection...

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Journal ArticleDOI
TL;DR: The expression of distinct sets of TLRs and the corresponding difference in reactivity to microbial molecules among subsets of pre-DCs and imDCs support the concept that they have developed through distinct evolutionary pathways to recognize different microbial antigens.
Abstract: Toll-like receptors (TLRs) are ancient microbial pattern recognition receptors highly conserved from Drosophila to humans. To investigate if subsets of human dendritic cell precursors (pre-DC), including monocytes (pre-DC1), plasmacytoid DC precursors (pre-DC2), and CD11c+ immature DCs (imDCs) are developed to recognize different microbes or microbial antigens, we studied their TLR expression and responses to microbial antigens. We demonstrate that whereas monocytes preferentially express TLR 1, 2, 4, 5, and 8, plasmacytoid pre-DC strongly express TLR 7 and 9. In accordance with these TLR expression profiles, monocytes respond to the known microbial ligands for TLR2 (peptidoglycan [PGN], lipoteichoic acid) and TLR4 (lipopolysaccharide), by producing tumor necrosis factor (TNF)-α and interleukin (IL)-6. In contrast, plasmacytoid pre-DCs only respond to the microbial TLR9-ligand, CpG-ODNs (oligodeoxynucleotides [ODNs] containing unmethylated CpG motifs), by producing IFN-α. CD11c+ imDCs preferentially express TLR 1, 2, and 3 and respond to TLR 2-ligand PGN by producing large amounts of TNF-α, and to viral double-stranded RNA-like molecule poly I:C, by producing IFN-α and IL-12. The expression of distinct sets of TLRs and the corresponding difference in reactivity to microbial molecules among subsets of pre-DCs and imDCs support the concept that they have developed through distinct evolutionary pathways to recognize different microbial antigens.

2,071 citations


"T-cell quality in memory and protec..." refers background in this paper

  • ...As TLR7 and TLR8 are expressed by plasmacytoid DCs and myeloid DCs respectivel...

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