Functional Diversity of T cells

Información del proyecto

FunDiT

Identificador del acuerdo de subvención: 802878

DOI

10.3030/802878

Proyecto cerrado

Fecha de la firma de la CE 10 Octubre 2018

Fecha de inicio 1 Enero 2019

Fecha de finalización 31 Diciembre 2023

Financiado con arreglo a

• EXCELLENT SCIENCE - European Research Council (ERC)

Coste total

€ 1 725 000,00

Aportación de la UE

€ 1 725 000,00

Coordinado por

USTAV MOLEKULARNI GENETIKY AV CR V.V.I.
Czechia

Periodic Reporting for period 4 - FunDiT (Functional Diversity of T cells)

Período documentado: 2023-07-01 hasta 2023-12-31

Resumen del contexto y de los objetivos generales del proyecto

A T-cell is a type of white blood cells, playing a key role in adaptive immunity. It is known that T cells represent a heterogeneous compartment with individual populations with unique functions. However, the functional diversity of T cells is poorly understood. Defining individual T-cell subsets and their unique functions will improve our understanding of the immune responses to infection, cancer as well as pathological autoimmune responses. The major aim of the project FunDiT was to characterize the T cell diversity to a great detail and to uncover the mechanisms leading to this diversity as well as functional differences between individual subsets and the mechanisms underlying their specific roles. We focused on the functions which particular subsets of T cells use to induce immune responses (conventional T cells) or suppress immune responses (regulatory T cells).
Understanding the pleiotropic roles of T cells and their specialized subtypes is required for uncovering the physiological and pathological mechanisms in infections, autoimmunity, and cancer. These mechanisms then could be targeted in novel therapies.
The overall objectives where to uncover the diversity of T cells, the function of individual subsets, and their major molecular mechanisms of action.

Conclusion: We were able to characterize emerging subsets of CD8+ T cells in mice, the connection between the self-reactivity of T cells and their functional diversity, the IL-17 receptor signaling pathways, the differential role of a kinase LCK for the function of CD8 and CD4 T cells, and novel role of ABIN1, a negative regulator of T-cell signaling.

Trabajo realizado desde el comienzo del proyecto hasta el final del período abarcado por el informe y los principales resultados hasta la fecha

We established the analysis of gene expression profiling on a single cell level in our laboratory. The results revealed novel T-cell subsets that were not previously described. Using our own data and publicly available data, we generated an atlas of steady-state CD8+ T cells and an atlas of CD8+ T cells during anti-viral responses. We further explored the diversity of CD8+ T cells by characterizing antigen-inexperienced memory-like T cells from different mouse strains, different conditions and even in feral mice.
We developed a unique mouse model that enables switching the T-cell specificities towards our model antigen. This mouse model will enable us to overcome technical difficulties in studying functional differences between T-cell subsets.
Part of the project focused on major effect mechanisms of T cells or their specific subsets. We characterized the functional role of coreceptor-LCK interaction in setting up the level of self-reactivity of CD4+ and CD8+ T cells. Moreover, we resolved a decades-long open question concerning the role of coreceptor-LCK interaction in T cells. Surprisingly, we observed that the coreceptor-bound LCK is largely dispensable for cytotoxic T cells, but is required for the development and function of helper T cells. We identified negative regulators of signaling via costimulatory T cell receptors and we are studying the physiological relevance of this regulation. In detail, we described a role of a protein ABIN1 in the negative regulation of T-cell signaling.
Th17 cells represent a specific subset of T cells that produce IL-17 cytokine to protect against fungal and bacterial infections. On the other hand, IL-17 is involved in autoimmune diseases such as psoriasis. We resolved how IL-17 signals including the proximal regulation of signaling. Moreover, we discovered a novel subunit of IL-17 receptor, CMTM4.
Regulatory T cells are another specific subset of T cells, which suppress the immune responses of other cell types. We discovered that the major mechanism how regulatory T cells inhibit the function of cytotoxic T cells in autoimmunity and cancer is taking up IL-2, which is a cytokine essential for the proliferation and effector cell formation by cytotoxic T cells. The results by us and others motivated us to formulate an opinion on how IL-2 leads to the induction of a very potent specific type of cytotoxic T cells which arise during IL-2-based therapies in cancer and chronic infections.
The results were published in seven publications and one preprint article. Moreover, at least 2 more articles using the data generated in the project will be published after the project is finished. The results were also presented at multiple international conferences and on PI’s social media account (Twitter/X).

Avances que van más allá del estado de la técnica e impacto potencial esperado (incluida la repercusión socioeconómica y las implicaciones sociales más amplias del proyecto hasta la fecha)

At least three of our results went beyond the state-of-the-art by providing a decent progress in our understanding of the immune system. First, the interaction between the T-cell co-receptors and LCK was described in 80’s and is often illustrated in text books, but its importance has not been addressed. We employed physiological models to finally resolve this question. Second, the receptors for all main signaling molecules in the immune system are largely known. Our identification and characterization of a novel subunit of the IL-17 receptor is a very rare achievement as it is something that has been overlooked by others. Third, we resolved the major mechanisms how regulatory T cells suppress cytotoxic T cells in autoimmunity and cancer. The re-analysis of data published by us and others lead us to formulate a novel conceptual framework for IL-2 therapies, concerning their efficiency and adverse effects.
From the technical point of view, we developed novel bioinformatic tools to uncover the diversity of T cells. We developed and optimized novel experimental techniques for the robust analysis of immune signaling pathways. We created a unique mouse model for studying the function of particular T-cell subsets.

T cell diversity revealed by single cell transcriptomics