IL-4-secreting CD4+ T cells are crucial to the development of CD8+ T-cell responses against malaria liver stages

Carvalho, Luzia H.; Sano, Gen Ichiro; Hafalla, Julius Clemence R.; Morrot, Alexandre; Lafaille, Maria A. Curotto de; Zavala, Fidel

doi:10.1038/nm0202-166

Cited by 219 publications

(193 citation statements)

References 39 publications

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“…Most importantly, the helper/inducer activity of RTS,S-immune CD4 ϩ T cells was evident only in cultures containing RTS,S-immune, but not naive CD8 ϩ T cells. Despite the preliminary nature of these observations, there is growing evidence that expansion as well as responses of Plasmodia Ag-generated CD8 ϩ T cells depend upon support from CD4 ϩ T cells (34,35).…”

Section: Cd4 ϩ and Cd8 ϩ T Cells Produce Ifn-␥mentioning

confidence: 99%

Protective Immunity Induced with Malaria Vaccine, RTS,S, Is Linked to Plasmodium falciparum Circumsporozoite Protein-Specific CD4+ and CD8+ T Cells Producing IFN-γ

Sun

Schwenk

White

et al. 2003

The Journal of Immunology

230

188

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The Plasmodium falciparum circumsporozoite (CS) protein-based pre-erythrocytic stage vaccine, RTS,S, induces a high level of protection against experimental sporozoite challenge. The immune mechanisms that constitute protection are only partially understood, but are presumed to rely on Abs and T cell responses. In the present study we compared CS protein peptide-recalled IFN-γ reactivity of pre- and RTS,S-immune lymphocytes from 20 subjects vaccinated with RTS,S. We observed elevated IFN-γ in subjects protected by RTS,S; moreover, both CD4+ and CD8+ T cells produced IFN-γ in response to CS protein peptides. Significantly, protracted protection, albeit observed only in two of seven subjects, was associated with sustained IFN-γ response. This is the first study demonstrating correlation in a controlled Plasmodia sporozoite challenge study between protection induced by a recombinant malaria vaccine and Ag-specific T cell responses. Field-based malaria vaccine studies are in progress to validate the establishment of this cellular response as a possible in vitro correlate of protective immunity to exo-erythrocytic stage malaria vaccines.

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Section: Cd4 ϩ and Cd8 ϩ T Cells Produce Ifn-␥mentioning

confidence: 99%

Protective Immunity Induced with Malaria Vaccine, RTS,S, Is Linked to Plasmodium falciparum Circumsporozoite Protein-Specific CD4+ and CD8+ T Cells Producing IFN-γ

Sun

Schwenk

White

et al. 2003

The Journal of Immunology

230

188

View full text Add to dashboard Cite

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“…CD4 T cells were important for the development of CD8 T cells specific for both T. gondii and malaria parasites (Gazzinelli et al 1991, Parker et al 1991). In the case of malaria (P. yoelii), it was possible to elegantly demonstrate that IL-4 secreted by CD4 T cells was crucial for the maturation, but not for the initial proliferation of specific CD8 T cells (Carvalho et al 2002).…”

Section: Conditions Of In Vivo Priming and Expansion Of Protective CDmentioning

confidence: 99%

Importance of CD8 T cell-mediated immune response during intracellular parasitic infections and its implications for the development of effective vaccines

Rodrigues

Boscardin

Vasconcelos

et al. 2003

An. Acad. Bras. Ciênc.

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Obligatory intracellular parasites such as Plasmodium sp, Trypanosoma cruzi, Toxoplasma gondii and Leishmania sp are responsible for the infection of hundreds of millions of individuals every year. These parasites can deliver antigens to the host cell cytoplasm that are presented through MHC class I molecules to protective CD8 T cells. The in vivo priming conditions of specific CD8 T cells during natural infection are largely unknown and remain as an area that has been poorly explored. The antiparasitic mechanisms mediated by CD8 T cells include both interferon-γ -dependent and -independent pathways. The fact that CD8 T cells are potent inhibitors of parasitic development prompted many investigators to explore whether induction of these T cells can be a feasible strategy for the development of effective subunit vaccines against these parasitic diseases. Studies performed on experimental models supported the hypothesis that CD8 T cells induced by recombinant viral vectors or DNA vaccines could serve as the basis for human vaccination. Regimens of immunization consisting of two different vectors (heterologous prime-boost) are much more efficient in terms of expansion of protective CD8 T lymphocytes than immunization with a single vector. The results obtained using experimental models have led to clinical vaccination trials that are currently underway.

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“…In addition, soluble signals may be involved in CD8 + T cell formation. It has been reported that IL-4-secreting CD4 + T cells are involved in the formation of memory CD8 + T cells and recent results revealed that IL-2 signals during the priming phase are necessary for the development of memory CD8 + T cells [13][14][15]. In addition, lymphocytic choriomeningitis virus (LCMV) immunization experiments with IL-2R-deficient T cells showed that induction and maintenance of specific T cells was independent of IL-2R signaling, whereas IL-2R signaling was crucial for the secondary expansion of memory CTL [16].…”

Section: Introductionmentioning

confidence: 99%

CD4⁺ T cell help improves CD8⁺ T cell memory by retained CD27 expression

2008

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CD4 + T cell help during the priming of CD8 + T lymphocytes imprints the capacity for optimal secondary expansion upon re-encounter with antigen. Helped memory CD8 + T cells rapidly expand in response to a secondary antigen exposure, even in the absence of T cell help and, are most efficient in protection against a re-infection. In contrast, helpless memory CTL can mediate effector function, but secondary expansion is reduced. How CD4 + T cells instruct CD8 + memory T cells during priming to undergo efficient secondary expansion has not been resolved in detail. Here, we show that memory CTL after infection with lymphocytic choriomeningitis virus are CD27 high whereas memory CTL primed in the absence of CD4 + T cell have a reduced expression of CD27. Helpless memory CTL produced low amounts of IL-2 and did not efficiently expand after restimulation with peptide in vitro. Blocking experiments with monoclonal antibodies and the use of CD27 -/-memory CTL revealed that CD27 ligation during restimulation increased autocrine IL-2 production and secondary expansion. Therefore, regulating CD27 expression on memory CTL is a novel mechanism how CD4 + T cells control CTL memory.Key words: CD27 Á CD4 T cell help Á Costimulation Á LCMV Á T cell memory IntroductionAfter an acute infection, the initial expansion of CTL is determined by a brief period of antigenic stimulation followed by a contraction to a stable pool of long-lived memory cells [1][2][3]. Memory CTL are characterized by an increased frequency of specific CD8 + T cells with a heightened sensitivity to an antigen that has been encountered previously. The cellular basis influencing memory CTL formation has been the focus of extensive research. Several studies highlighted the importance of CD4 + T cells in the generation of CTL memory [4][5][6]. Memory T lymphocytes that are primed in the absence of CD4 + T cell help have a reduced proliferation capacity. In addition, the production of acute effector cytokines and IL-2 are reduced [7]. "Unhelped" CD8 + T cells die upon in vitro re-activation, due to the expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is not expressed by "helped" CD8 + memory T cells [8].The mechanisms how CD4 + T cell help drives CD8 + T cell memory has not been resolved in detail. Mice deficient for CD40L have CD8 + memory T cells with reduced function. The CD40-CD40L interaction may be involved in the generation of CTL memory via two mechanisms. First, CD4 + T cells expressing CD40L activate APC through CD40 and these "licensed" APC are then able to drive CD8 + T cell responses [9][10][11]. Secondly, CD4 + T cells expressing CD40L may directly deliver help to CD8 + T cells [7]. Besides the CD40-CD40L interaction, other receptor-ligand interactions such as the CD27-CD70 interaction may be important for generating functional CD8 + memory T cells [12]. In addition, soluble signals may be involved in CD8 + T cell formation. It has been reported that IL-4-secreting CD4 + T cells are involved in the formation of memo...

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IL-4-secreting CD4+ T cells are crucial to the development of CD8+ T-cell responses against malaria liver stages

Cited by 219 publications

References 39 publications

Protective Immunity Induced with Malaria Vaccine, RTS,S, Is Linked to Plasmodium falciparum Circumsporozoite Protein-Specific CD4+ and CD8+ T Cells Producing IFN-γ

Protective Immunity Induced with Malaria Vaccine, RTS,S, Is Linked to Plasmodium falciparum Circumsporozoite Protein-Specific CD4+ and CD8+ T Cells Producing IFN-γ

Importance of CD8 T cell-mediated immune response during intracellular parasitic infections and its implications for the development of effective vaccines

CD4⁺ T cell help improves CD8⁺ T cell memory by retained CD27 expression

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IL-4-secreting CD4+ T cells are crucial to the development of CD8+ T-cell responses against malaria liver stages

Cited by 219 publications

References 39 publications

Protective Immunity Induced with Malaria Vaccine, RTS,S, Is Linked to Plasmodium falciparum Circumsporozoite Protein-Specific CD4+ and CD8+ T Cells Producing IFN-γ

Protective Immunity Induced with Malaria Vaccine, RTS,S, Is Linked to Plasmodium falciparum Circumsporozoite Protein-Specific CD4+ and CD8+ T Cells Producing IFN-γ

Importance of CD8 T cell-mediated immune response during intracellular parasitic infections and its implications for the development of effective vaccines

CD4+ T cell help improves CD8+ T cell memory by retained CD27 expression

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CD4⁺ T cell help improves CD8⁺ T cell memory by retained CD27 expression