Targeting dendritic cell plasticity to modulate antigen-specific T cell recall responses in human

Project Information

plasTCD

Grant agreement ID: 101031986

DOI

10.3030/101031986

Project closed

EC signature date 15 March 2021

Start date 1 May 2021

End date 30 April 2023

Funded under

• EXCELLENT SCIENCE - Marie Skłodowska-Curie Actions

Total cost

€ 196 707,84

EU contribution

€ 196 707,84

Coordinated by

INSTITUT NATIONAL DE LA SANTE ET DE LA RECHERCHE MEDICALE
France

Periodic Reporting for period 1 - plasTCD (Targeting dendritic cell plasticity to modulate antigen-specific T cell recall responses in human)

Reporting period: 2021-05-01 to 2023-04-30

Summary of the context and overall objectives of the project

The human immune system has the ability to fight various infectious diseases. A hallmark of the immune system is the generation of an immunological memory. Memory cells can be detected in humans for several decades following an infection or a vaccination. While the generation of memory T cells have been well described, a significant gap of knowledge remains on how immune cells cooperate to reactivate the immunological memory. A better understanding of these biological mechanisms can have an important impact on the design of vaccines and the generation of long-term protection against pathogens. In this interdisciplinary program, we used an experimental systematic approach, together with forefront technologies and integrative analyses, to investigate the biological mechanisms by which key human immune cells cooperate to effectively reactivate memory T cells. We identified unprecedented key cellular and molecular mechanisms associated with the functional reactivation and proliferation of memory T cells. From this work, several original scientific publications are currently under preparations.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

During this program, we have successfully developed an innovative miniaturized in vitro co-culture system to systematically interrogate the dialogue between various type of innate immune cells (which are immune sensors detecting the first events of an infection), and memory T cells.
We used this experimental system in the context of Influenza A virus infection. We chose Influenza A virus as a model because it triggers strong innate immune responses and generates memory T cells that we can use as a functional readout in our experimental approaches. We were then able to characterize and systematically compare the diversification of several innate immune cell subsets in response to Influenza challenge (i.e. expression of immune checkpoints proteins and secretion of cytokines). In addition, by comparing the different innate immune cells for their ability to reactivate memory T cells, we uncovered the important role of a particular innate immune cell subset that induces higher functional activation and proliferation rate of memory T cells, as compared to the other innate cells. These results are important as this innate cell subset could be targeted by next-generation vaccines in order to stimulate memory T cells. We are currently extending those results by the analysis of the gene expression and the clonal diversity of the memory T cells, in order to determine the molecular mechanisms leading to their functional activation and proliferation.
As of today, we have presented these results at several seminars and scientific gatherings, and several original publications are currently under preparation.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

Seasonal epidemics caused by respiratory viruses can lead to important morbidity and mortality, as well as important socio-economic losses. Correlate of immune protection against infection and severe disease includes the presence of broad and potent memory T cells, elicited from previous natural infections and/or vaccination campaigns. Boosting these responses may represent a valuable strategy to improve current vaccine immune protection.
By the end of our program, we expect to provide novel biological insights about the cellular and molecular mechanisms used by innate immune cells to effectively reactivate memory T cells. Such information could considerably inform the design of next-generation vaccines.

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