Low Dose <i>Leishmania major</i> Promotes a Transient T Helper Cell Type 2 Response That Is Down-regulated by Interferon γ–producing CD8+ T Cells

Uzonna, Jude E.; Joyce, Karen L.; Scott, Phillip

doi:10.1084/jem.20040172

Cited by 142 publications

(153 citation statements)

References 48 publications

(65 reference statements)

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“…This highlights a novel role that allows the transmission of CD8 1 T-cell-mediated Th1-inducing signals without the need for physical interaction with infiltrating monocytes, similar to other bystander-mediated crosstalk seen in infectious models [23,24]. This may also explain the importance of CD8 1 T cells in microbial infections [10][11][12]25], since TNF-a and NO production by Tip-DCs are key effectors in pathogen clearance [3].…”

Section: Discussionmentioning

confidence: 82%

“…Since the differentiation of monocytes into DCs or macrophages relies on the microenvironment, the presence of different T-cell types and cytokines is a critical feature in determining the differentiation outcome [6]. Besides their cytotoxic function [7], CD8 1 T cells have been shown to regulate allergic diseases by inhibiting the development of Th2 responses [8,9] and driving Th1 immunity in microbial infections [10][11][12]. CD8 1 T cells exert this pro-Th1 influence through a feedback mechanism during their interactions with DCs.…”

Section: Introductionmentioning

confidence: 99%

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Human CD8⁺ T cells drive Th1 responses through the differentiation of TNF/iNOS‐producing dendritic cells

et al. 2011

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TNF/iNOS-producing dendritic cells (Tip-DCs) have been shown to arise during inflammation and are important mediators of immune defense. However, it is still relatively unclear which cell types contribute to their differentiation. Here we show that CD8 1 T cells, through the interaction with DCs, can induce the rapid development of human monocytes into Tip-DCs that express high levels of TNF-a and iNOS. Tip-DCs exhibited T-cell priming ability, expressed high levels of MHC class II, upregulated co-stimulatory molecules CD40, CD80, CD86, toll-like receptors TLR2, TLR3, TLR4, chemokine receptors CCR1 and CX3CR1 and expressed the classical mature DC marker, CD83. Differentiation of monocytes into Tip-DCs was partially dependent on IFN-c as blocking the IFN-c receptor on monocytes resulted in a significant decrease in CD40 and CD83 expression and in TNF-a production. Importantly, these Tip-DCs were capable of further driving Th1 responses by priming naive CD4 1 T cells for proliferation and IFN-c production and this was partially dependent on Tip-DC production of TNF-a and NO. Our study hence identifies a role for CD8 1 T cells in orchestrating Th1-mediating signals through the differentiation of monocytes into Th1-inducing Tip-DCs.Keywords: CD8 1 T cells . Cell differentiation . DCs . Monocytes . T-helper cells Supporting Information available online IntroductionDCs bridge innate and adaptive immunity by incorporating signals from environmental cues to drive the activation of T cells [1]. While DCs display a dendritic form and exhibit DC functions during steady state, inflammatory DCs, derived from CCR2 1 monocytes, only appear as a consequence of infection or inflammation [2]. Recent studies in mice have identified a subset of inflammatory DCs, known as TNF/iNOS-producing DCs (Tip-DCs), that are important for the clearance of Listeria monocytogenes bacteria [3]; influenza virus [4]; and regulation of IgA production in mucosal immunity [5]. Since the differentiation of monocytes into DCs or macrophages relies on the microenvironment, the presence of different T-cell types and cytokines is a critical feature in determining the differentiation outcome [6]. Besides their cytotoxic function [7], CD8 1 T cells have been shown to regulate allergic diseases by inhibiting the development of Th2 responses [8,9] and driving Th1 immunity in microbial infections [10][11][12]. CD8 1 T cells exert this pro-Th1 influence through a feedback mechanism during their interactions with DCs. CD8 1 T cells utilize a variety of factors, including IFN-g, GM-CSF, TNF-a and CD40L to activate DCs for the production of 13,14], the key cytokine for Th1 immunity [15]. Importantly, CD8 1 T cells were shown to interact with DCs in both lymph nodes [16] and peripheral tissue sites [4,17] where they exert their pro-Th1 influence.Previous studies have shown that CD8 1 T cells are able to infiltrate quickly into inflamed sites [18] that may facilitate their early interaction with DCs. In human psoriasis studies, the administration of alefacept, which ...

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Section: Discussionmentioning

confidence: 82%

Section: Introductionmentioning

confidence: 99%

Human CD8⁺ T cells drive Th1 responses through the differentiation of TNF/iNOS‐producing dendritic cells

et al. 2011

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“…how CD8 T cells were able to skew a Th2 response towards a protective Th1 response during low-dose Leishmania major infection [8]. Similarly, the depletion of CD8 T cells during DNA vaccination is associated with a marked decrease in IFN-c-producing CD4 T cells [9].…”

Section: Discussionmentioning

confidence: 99%

“…However, their ability to promote Th1 responses has also been described. In vivo, CD8 T cells have been shown to be essential for the induction of protective Th1 responses against microbial infections [8][9][10]. Likewise, CD8 T cells can also inhibit the development of allergic Th2 IgE responses [11,12].…”

Section: Introductionmentioning

confidence: 99%

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CD40L‐expressing CD8 T cells prime CD8α⁺ DC for IL‐12p70 production

et al. 2008

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CD8a + DC are implicated as the principle DC subset for cross-presentation and crosspriming of cytotoxic CD8 T cell responses. In this study, we demonstrate another unique facet of the CD8a + DC and CD8 T cell relationship, by showing that CD8 T cells reciprocally activate CD8a + DC, but not CD8a -DC, for IL-12p70 production, the key Th1-promoting cytokine. This effect was observed during an antigen-specific interaction between DC and activated CD8 T cells, along with secondary TLR stimulation of DC by LPS. Activated CD8 T cells use a combination of IFN-c and CD40L, which is rapidly up-regulated poststimulation, to prime DC for IL-12p70 production during an antigen-specific response. Our results suggest that the interaction between CD8a + DC and antigen-primed CD8 T cells may form an important component of Th1-mediated immunity through the induction of IL-12p70. Key words: CD8 T cells Á Dendritic cells Á IL-12p70Introduction DC are essential for the activation and polarization of T cells during an adaptive immune response [1,2]. DC respond to stimulatory signals from microbes and inflammatory mediators and mature into professional antigen-presenting cells that prime the adaptive immune system [3,4]. DC activity is also influenced through direct and indirect interaction with other effector immune cells, which results in the delivery of "feedback" signals that can influence the activation status of the DC and thus the outcome of the adaptive immune response [5][6][7]. CD8 T cells are principally known for their role in cytotoxic killing. However, their ability to promote Th1 responses has also been described. In vivo, CD8 T cells have been shown to be essential for the induction of protective Th1 responses against microbial infections [8][9][10]. Likewise, CD8 T cells can also inhibit the development of allergic Th2 IgE responses [11,12]. CD8 T cells can have a direct impact on DC during their interaction, inducing DC to mature [13], and enhancing their Th1-polarizing capabilities by augmenting their ability to produce 14,15].IL-12p70 is a heterodimeric pro-inflammatory cytokine that plays a central role in Th1 immunity, acting on T cells and NK cells by inducing proliferation, cytotoxic function and IFN-c production [16]. IL-12p70 production by DC during T cell priming is crucial for the development of Th1 responses [16][17][18]. Hence, control of DC IL-12p70 production is important for the development of Th1 immunity.Previous reports on CD8 T cell-mediated IL-12p70 production utilized DC generated from monocytes or bone marrow progenitors using 14,15]. These DC are now thought to appear only under inflammatory conditions [19]. They differ markedly from DC that reside in lymphoid organs, and hence do not necessarily reflect events that occur with lymphoid resident DC. Splenic DC comprise of a heterogeneous population of cells with different phenotypes and functional characteristics [20]. It is unknown whether CD8 T cells could possibly modulate IL-12p70 production with splenic resident DC, or whether CD8 T cellme...

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Immunity to Protozoa

Velázquez

Dominguez

Garzon

et al. 2018

Encyclopedia of Life Sciences

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Protozoan parasites are microorganisms that live and feed at the expense of a host. Parasites can cause diseases in humans and are worldwide distributed, causing high morbidity and mortality. This article describes the most important defence mechanisms against protozoan parasites of clinical relevance ( Plasmodium spp., Leishmania spp., Toxoplasma gondii , Trypanosoma cruzi , Entamoeba histolytica and Giardia lamblia ). Protozoans exhibit a high heterogeneity in morphologies and antigenic expression, which is reflected in the different immune responses induced during the infection process. The first line of defence is the mechanisms of the innate immune response as physical and chemical barriers. However, in most cases, the adaptive humoural and cellular responses are implicated in controlling the infection. On the other hand, parasites have developed mechanisms to evade the immune response, hindering the development of vaccines, which offers a broad spectrum of protection among species. Key Concepts Parasitosis comprises a set of very diverse diseases, caused by different types of parasitic microorganisms. Protozoan infections can be acquired either through direct contact or through vectors. Malaria is the deadliest protozoan infection worldwide. The immune response is divided into two branches: innate and adaptive immunity. Protozoan parasites have developed strategies to evade the immune response. To date, there has been an imminent necessity to develop efficient vaccines against main protozoan infections.

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Low Dose Leishmania major Promotes a Transient T Helper Cell Type 2 Response That Is Down-regulated by Interferon γ–producing CD8+ T Cells

Cited by 142 publications

References 48 publications

Human CD8⁺ T cells drive Th1 responses through the differentiation of TNF/iNOS‐producing dendritic cells

Human CD8⁺ T cells drive Th1 responses through the differentiation of TNF/iNOS‐producing dendritic cells

CD40L‐expressing CD8 T cells prime CD8α⁺ DC for IL‐12p70 production

Immunity to Protozoa

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Low Dose Leishmania major Promotes a Transient T Helper Cell Type 2 Response That Is Down-regulated by Interferon γ–producing CD8+ T Cells

Cited by 142 publications

References 48 publications

Human CD8+ T cells drive Th1 responses through the differentiation of TNF/iNOS‐producing dendritic cells

Human CD8+ T cells drive Th1 responses through the differentiation of TNF/iNOS‐producing dendritic cells

CD40L‐expressing CD8 T cells prime CD8α+ DC for IL‐12p70 production

Immunity to Protozoa

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Human CD8⁺ T cells drive Th1 responses through the differentiation of TNF/iNOS‐producing dendritic cells

Human CD8⁺ T cells drive Th1 responses through the differentiation of TNF/iNOS‐producing dendritic cells

CD40L‐expressing CD8 T cells prime CD8α⁺ DC for IL‐12p70 production