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Understanding the Human T Cell Response to Dengue Virus

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Book cover Dengue and Zika: Control and Antiviral Treatment Strategies

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1062))

Abstract

Our understanding of how T cells respond to dengue virus has greatly advanced in the last decade but important questions still remain unanswered. Dengue virus infection elicits a broad anti-viral T cell response with NS3, NS4b and NS5 being the main targets for CD8+ T cells, which dominate the response while the structural proteins capsid, envelope and the secreted protein NS1 are the preferential targets for CD4+ T cells. Upon T cell activation during acute dengue infection, dengue-specific T cells acquire expression of the skin-homing marker cutaneous associated antigen (CLA) and they can be found at high frequencies in the skin of infected patients. This suggests that the skin represents an important site for the immuno surveillance of dengue virus. The immunoprotective role of skin-homing dengue-specific T cells, their potential involvement in pathological skin manifestations and their long-term persistence as tissue resident T cells to provide immediate onsite protection are open questions that we are currently investigating. The contribution of pre-existing dengue-specific T cells towards protective immunity and/or immunopathology during secondary dengue infection remains a major knowledge gap. The evidence supporting these opposing outcomes and our current understanding of the characteristics of the human T cell response to dengue virus will be discussed.

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Acknowledgments

This work is supported by a Cooperative Basic Research Grant- New Investigator Grant (CBRG-NIG R-913-301-289-213) awarded by the Singapore National Medical Research Council to Laura Rivino.

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Authors and Affiliations

  1. Program in Emerging Infectious Diseases, Duke-NUS Medical School, Singapore, Singapore

    Laura Rivino

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  1. Laura Rivino
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Correspondence to Laura Rivino .

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Editors and Affiliations

  1. Institute of Biochemistry, University of Lübeck, Lübeck, Germany

    Rolf Hilgenfeld

  2. Emerging Infectious Diseases Program, Duke-NUS Medical School Singapore, Singapore, Singapore

    Subhash G. Vasudevan

Discussion of Chapter 17 in Dengue and Zika: Control and Antiviral Treatment Strategies

Discussion of Chapter 17 in Dengue and Zika: Control and Antiviral Treatment Strategies

This discussion was held at the 2nd Advanced Study Week on Emerging Viral Diseases at Praia do Tofo, Mozambique.Transcribed by Hilgenfeld R and Vasudevan SG (Eds); approved by Dr. Laura Rivino.

  • Anuja Mathew: So you found higher frequencies of CD8+ T cells in the skin. Do you have an hypothesis of why you would see a preference for CD8+ or CD4+ T cells?

  • Laura Rivino: We have preliminary data showing that the dengue-specific T cells that we find in the skin are mostly CD8+ T cells, so we think these cells could account in part for the increase of total CD8+ T cells that we find during acute dengue in the skin. We do not expect this influx of CD8+ T cells to comprise of only dengue-specific T cells. We know, for example from studies performed by us and others that in the blood of acute dengue patients there is also “bystander-activation” of CD8+ T cells that are specific for non-related, persistent viruses such as HCMV and EBV. So the influx of CD8+ T cells that occurs in the skin of acute dengue patients could comprise of both dengue-specific and “bystander-activated” T cells.

  • This higher frequncies of CD8+ T cells that we observe in the skin of acute dengue patients was not surprising to us since for other skin viral infections, such as Herpex simplex virus, the anti-viral response at the skin level is mainly a CD8+ T cell response.

  • Katja Fink: The cytokines that you find in the blister fluid are more or less the same as what is observed in the plasma or in the skin?

  • Laura Rivino: No. So the increase in pro-inflammtory cytokines is more pronounced in the skin compared to the blood. We have done quite a lot of cytokine profiling from the plasma of dengue patents and the increase in pro-inflammatory cytokines at the time points we look at are obvious only for the more severe dengue cases. We generally do not see significant increases of these cytokines in the blood, especially of TNF-α.

  • Katja Fink: So you compared skin and blood samples from the same patients?

  • Laura Rivino: Yes.

  • Aravinda da Silva: Were these cases primary infections?

  • Laura Rivino: Most of our patients are experiencing secondary infections. We had few primary infections so it’s difficult to really make a statement, but when I looked seperately at patients with primary and secondary infection I didn’t see a very big difference in terms of immunodominance of the different dengue proteins. The immunodominance was similar in primary and secondary cases and also for different dengue serotypes as well.

  • Aravinda da Silva: Right, but in terms of seeing the cells so early in the skin by day four of onset of symptoms, it seems very fast for a primary response. Do you see it that fast and in those numbers even in primary infection?

  • Laura Rivino: We don’t have the data yet of which patients were experiencing primary or secondary infection for the skin samples.

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Rivino, L. (2018). Understanding the Human T Cell Response to Dengue Virus. In: Hilgenfeld, R., Vasudevan, S. (eds) Dengue and Zika: Control and Antiviral Treatment Strategies. Advances in Experimental Medicine and Biology, vol 1062. Springer, Singapore. https://doi.org/10.1007/978-981-10-8727-1_17

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