CD4 Help Regulates Expression of Crucial Genes Involved in CD8 T Cell Memory and Sensitivity to Regulatory Elements

Rapetti, Laetitia; Meunier, Sylvain; Pontoux, Christiane; Tanchot, Corinne

doi:10.4049/jimmunol.181.1.299

Cited by 19 publications

(14 citation statements)

References 66 publications

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“…Using the tetramer assay, all the mice were monitored for CTL survival and memory CTL expansion after boosting with DCova (Figure 1b). In both WT and CD4 + T cell-deficient mice, CTLs which received help during priming demonstrated significantly stronger survival and expansion upon boosting ( P <0.05), corroborating previous observations [6,7,9,10]. Interestingly, transitionally helped effector CTLs also survived and expanded more efficiently than unhelped CTLs both in WT and CD4 + T cell-deficient mice ( P <0.05).…”

Section: Resultssupporting

confidence: 88%

Th Cells Promote CTL Survival and Memory via Acquired pMHC-I and Endogenous IL-2 and CD40L Signaling and by Modulating Apoptosis-Controlling Pathways

Umeshappa

Xie

et al. 2013

PLoS ONE

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Involvement of CD4+ helper T (Th) cells is crucial for CD8+ cytotoxic T lymphocyte (CTL)-mediated immunity. However, CD4+ Th’s signals that govern CTL survival and functional memory are still not completely understood. In this study, we assessed the role of CD4+ Th cells with acquired antigen-presenting machineries in determining CTL fates. We utilized an adoptive co-transfer into CD4+ T cell-sufficient or -deficient mice of OTI CTLs and OTII Th cells or Th cells with various gene deficiencies pre-stimulated in vitro by ovalbumin (OVA)-pulsed dendritic cell (DCova). CTL survival was kinetically assessed in these mice using FITC-anti-CD8 and PE-H-2Kb/OVA257-264 tetramer staining by flow cytometry. We show that by acting via endogenous CD40L and IL-2, and acquired peptide-MHC-I (pMHC-I) complex signaling, CD4+ Th cells enhance survival of transferred effector CTLs and their differentiation into the functional memory CTLs capable of protecting against highly-metastasizing tumor challenge. Moreover, RT-PCR, flow cytometry and Western blot analysis demonstrate that increased survival of CD4+ Th cell-helped CTLs is matched with enhanced Akt1/NF-κB activation, down-regulation of TRAIL, and altered expression profiles with up-regulation of prosurvival (Bcl-2) and down-regulation of proapoptotic (Bcl-10, Casp-3, Casp-4, Casp-7) molecules. Taken together, our results reveal a previously unexplored mechanistic role for CD4+ Th cells in programming CTL survival and memory recall responses. This knowledge could also aid in the development of efficient adoptive CTL cancer therapy.

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Section: Resultssupporting

confidence: 88%

Th Cells Promote CTL Survival and Memory via Acquired pMHC-I and Endogenous IL-2 and CD40L Signaling and by Modulating Apoptosis-Controlling Pathways

Umeshappa

Xie

et al. 2013

PLoS ONE

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“…Indeed, these studies have shown that CD8 + T cells primed under helpless conditions have severe defects in the expression of crucial genes related to proliferation, survival and cytotoxic functions (Rapetti et al, 2008). We have now extended these observations to demonstrate that T-cell responses generated in helpless mice following vaccination are qualitatively inferior when compared with helped mice and fail to afford resistance against viral challenge.…”

Section: Epstein-barr Virus (Ebv) Vaccinesupporting

confidence: 50%

Delineating the role of CD4+ T cells in the activation of human cytomegalovirus-specific immune responses following immunization with Ad-gBCMVpoly vaccine: implications for vaccination of immunocompromised individuals

Zhong

Khanna

2010

Journal of General Virology

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Reconstitution of the virus-specific CD8 + T-cell response is crucial for the prevention of human cytomegalovirus (CMV)-associated pathogenesis in transplant patients and human immunodeficiency virus-infected individuals. Although adoptive T-cell immunotherapy has been used successfully in various clinical settings, prophylactic vaccination remains the most amenable strategy to prevent CMV disease. However, vaccination in clinical settings where the host is severely immunocompromised due to the loss of CD4 + T cells remains a significant challenge. This study investigated the efficacy of a chimeric CMV vaccine in a model setting that allowed studies on the generation of CD8 + T-cell memory responses in a transient CD4 + T-cell-deficient setting similar to that seen in immunocompromised patients. Immunization with an adenoviral CMV vaccine under transient helpless (complete CD4 + T-cell depletion) or help-deficient (partial CD4 + T-cell depletion) conditions demonstrated that induction of the effector CD8 + T-cell and humoral responses was almost completely eliminated under helpless conditions, and was gradually regained with the recovery of CD4 + T cells. However, this response failed to protect the host from viral infection, suggesting that lack of CD4 + T cells during vaccination can significantly impair the priming and maturation of CMV-specific immune responses. Furthermore, although the induction of CMV-specific immune responses was also significantly reduced in a help-deficient environment, these primed effector cells could mature normally and generate long-term polyfunctional memory responses capable of restricting virus replication in vivo. These results highlight the importance of monitoring CD4 + T-cell numbers before vaccination for the successful implementation of a CMV vaccine in an immunocompromised setting.

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“…Increasing evidence from animal studies and clinical trials have suggested that effective adoptive cellular immunotherapy (ACI) is not limited to the use of CD8 + T cells and may be enhanced by the use of antigen-specific CD4 + T cells (24–25). For examples, immunotherapy using tumor-specific CD8 + T cells in CD4-deficient MHC II −/− mice resulted in regression of pulmonary metastases, but did not result in long-term antitumor immunity and tumor eventually recurred (26, 27).…”

Section: Discussionmentioning

confidence: 99%

Identification of Melanoma-reactive CD4+ T-Cell Subsets From Human Melanoma Draining Lymph Nodes

Zhang

Graor

Lü

et al. 2016

Journal of Immunotherapy

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Our laboratory has previously demonstrated that melanoma draining lymph node (MDLN) samples from stage III patients contained both CD4+ and CD8+ T cells that can be readily expanded to mediate tumor cell apoptosis in vitro and improve survival in mice bearing human melanoma xenografts. In this study, we investigated whether MDLN T cells contain melanoma-reactive CD4+ T cell compartment and what they are. In order to test this, we performed multi-parametric (11-color and 6-color) FACS analyses to monitor phenotypic and functional property of CD4+ T cells in response to melanoma cell antigen re-exposure. Our results have demonstrated that the antigen re-exposure could result in a generation of CD4+CCR7+CD62L+CD27− T cell subsets with various effector cell-like properties. Within the CD4+CCR7+CD62L+CD27− T cell compartment, in response to antigen re-exposure, some of the cells expressed significantly up-regulated CD40L and/or CXCR5, and some of them expressed significantly up-regulated IL-2 and/or TNF-α. This may suggest the existence of melanoma reactive CD4+ “effector-precursor” cells within the expanded MDLN cells and their differentiation into various effector lineages in response to antigen re-stimulation. Recent clinical trials have demonstrated that effective adoptive cellular immunotherapy (ACI) maybe enhanced by antigen specific CD4+ T cells. Therefore, results of this study may significantly benefit innovative design of ACI that can potentially mediate enhanced and durable clinical responses.

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CD4 Help Regulates Expression of Crucial Genes Involved in CD8 T Cell Memory and Sensitivity to Regulatory Elements

Cited by 19 publications

References 66 publications

Th Cells Promote CTL Survival and Memory via Acquired pMHC-I and Endogenous IL-2 and CD40L Signaling and by Modulating Apoptosis-Controlling Pathways

Th Cells Promote CTL Survival and Memory via Acquired pMHC-I and Endogenous IL-2 and CD40L Signaling and by Modulating Apoptosis-Controlling Pathways

Delineating the role of CD4+ T cells in the activation of human cytomegalovirus-specific immune responses following immunization with Ad-gBCMVpoly vaccine: implications for vaccination of immunocompromised individuals

Identification of Melanoma-reactive CD4+ T-Cell Subsets From Human Melanoma Draining Lymph Nodes

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