CD4-positive T lymphocytes are required for the generation of the primary but not the secondary CD8-positive cytolytic T lymphocyte response to herpes simplex virus in C57BL/6 mice

Jennings, Stephen R.; Bonneau, Robert H.; Smith, Patrick M.; Wolcott, R. Michael; Chervenak, Robert

doi:10.1016/0008-8749(91)90194-g

Cited by 120 publications

(73 citation statements)

References 46 publications

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“…IL-2 has been previously shown to be important for the differentiation of HSV-specific CD8 + CTL precursors into functional effector cells during the acute phase of primary HSV infection in adult mice [32]. Thus, it is possible that the low levels of IL-2 in culture and the decreased expression of CD25 on neonatal CD8 + T cells we observed resulted in reduced expansion of HSV-specific CD8 + T cells and/ or impaired differentiation into a functional phenotype.…”

Section: Discussionmentioning

confidence: 74%

HSV induces an early primary Th1 CD4 T cell response in neonatal mice, but reduced CTL activity at the time of the peak adult response

Evans

Jones

2005

Eur J Immunol

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Neonates are highly susceptible to HSV. In this study, we analyzed the primary neonatal cell-mediated response to HSV at the site of T cell activation, the draining lymph nodes (LN), and examined the effects of dose and the ability of HSV to replicate on the strength and character of this response. Neonatal mice mounted a predominantly Th1 cytokine (IFN-c) response at all doses of a replication-competent thymidine kinase-negative HSV-2 strain (186DKpn) and at high doses of a replication-defective HSV-2 virus (dl5-29, UL5-/UL29 -). Both neonates and adults showed increased production of Th2 cytokines (IL-4 and/or IL-5) at high doses of the replication-defective or inactivated HSV strains. An age-dependent difference in the strength of the Th1 response was noted, with neonates mounting adult-like responses at low but not high doses of HSV. Neonatal mice also showed impaired CD8 + T cell activation and reduced HSV-specific CTL effector function at the time of the peak adult response. These studies are the first to highlight the impaired primary neonatal T cell response to HSV in the LN.

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Section: Discussionmentioning

confidence: 74%

HSV induces an early primary Th1 CD4 T cell response in neonatal mice, but reduced CTL activity at the time of the peak adult response

Evans

Jones

2005

Eur J Immunol

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“…In support of this model is the observation that c-rel Ϫ/Ϫ mice can generate CTL immunity to HSV (Fig. 1) and influenza virus (15), where neither CTL response requires CD4 T cell help (35,36). Licensing of the APC with viral products that overcome the requirement for CD4 T cell activation renders the Rel-dependent signaling pathway unnecessary.…”

Section: Discussionmentioning

confidence: 87%

The Cross-Priming APC Requires a Rel-Dependent Signal to Induce CTL

Mintern

Belz

Gerondakis

et al. 2002

The Journal of Immunology

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Induction of OVA-specific CTL by cross-priming requires help from CD4 T cells, which use CD154 to signal CD40 on the APC. To further dissect the molecular pathways involved in cross-priming, we examined the role of Rel, an NF-κB family member. c-rel−/− mice failed to generate OVA-specific CTL by cross-priming, but could induce CTL to HSV-1. Using chimeric mice, Rel expression was shown to be required by the APC, but not by the T cells. Notably, the deficiency in Rel could be overcome by triggering CD40, implying that the APC required Rel before receipt of the CD40 signal. These data suggest that the cross-priming APC must receive two signals before it can stimulate CTL. The first signal is Rel dependent and is required before activation of CD4 helper T cells, which then deliver the second signal using CD154 to trigger CD40.

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“…Help from CD4 T cells (5-7) has been asserted to be necessary for the development of an optimal CTL response, particularly in the context of mild inflammatory conditions, such as those found in tumors, dendritic cell (DC)-based vaccination, immunizations with proteins or peptides, or in certain virus infections, such as HSV or influenza virus infection (8)(9)(10). In these settings, the lack of CD4 T cell help during priming results in defective memory CTLs that mediate effector functions but do not undergo a second round of clonal expansion on Ag rechallenge (7,11,12).…”

mentioning

confidence: 99%

CD8 T Cell Priming in the Presence of IFN-α Renders CTLs with Improved Responsiveness to Homeostatic Cytokines and Recall Antigens: Important Traits for Adoptive T Cell Therapy

Hervás-Stubbs

Mancheño

Riezu-Boj

et al. 2012

The Journal of Immunology

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Previous mouse and human studies have demonstrated that direct IFN-α/β signaling on naive CD8 T cells is critical to support their expansion and acquisition of effector functions. In this study, we show that human naive CD8 T cells primed in the presence of IFN-α possess a heightened ability to respond to homeostatic cytokines and to secondary Ag stimulation, but rather than differentiating to effector or memory CTLs, they preserve nature-like phenotypic features. These are qualities associated with greater efficacy in adoptive immunotherapy. In a mouse model of adoptive transfer, CD8 T cells primed in the presence of IFN-α are able to persist and to mediate a robust recall response even after a long period of naturally driven homeostatic maintenance. The long-lasting persistence of IFN-α–primed CD8 T cells is favored by their enhanced responsiveness to IL-15 and IL-7, as demonstrated in IL-15−/− and IL-7−/− recipient mice. In humans, exposure to IFN-α during in vitro priming of naive HLA-A2+ CD8 T cells with autologous dendritic cells loaded with MART126–35 peptide renders CD8 T cells with an improved capacity to respond to homeostatic cytokines and to specifically lyse MART1-expressing melanoma cells. Furthermore, in a mouse model of melanoma, adoptive transfer of tumor-specific CD8 T cells primed ex vivo in the presence of IFN-α exhibits an improved ability to contain tumor progression. Therefore, exposure to IFN-α during priming of naive CD8 T cells imprints decisive information on the expanded cells that can be exploited to improve the efficacy of adoptive T cell therapy.

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CD4-positive T lymphocytes are required for the generation of the primary but not the secondary CD8-positive cytolytic T lymphocyte response to herpes simplex virus in C57BL/6 mice

Cited by 120 publications

References 46 publications

HSV induces an early primary Th1 CD4 T cell response in neonatal mice, but reduced CTL activity at the time of the peak adult response

HSV induces an early primary Th1 CD4 T cell response in neonatal mice, but reduced CTL activity at the time of the peak adult response

The Cross-Priming APC Requires a Rel-Dependent Signal to Induce CTL

CD8 T Cell Priming in the Presence of IFN-α Renders CTLs with Improved Responsiveness to Homeostatic Cytokines and Recall Antigens: Important Traits for Adoptive T Cell Therapy

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