Development and function of conventional and non-conventional lymphocytes

The three types of antigen receptors – B cell receptor (BCR), αβT cell receptor (TCR), and γδTCR – characterize the corresponding lymphocyte populations that form the adaptive immune system in jawed vertebrates. The random generation of antigen receptors inevitably results in the production of self-reactive receptors by a fraction of developing lymphocytes. Such cells have to be functionally or physically inactivated at the site of lymphocyte development (central tolerance) or in the secondary lymphoid organs (peripheral tolerance). In the case of T cell development in the thymus, some of autoreactive thymocytes are eliminated by negative selection, while others undergo agonist selection to innate-like lineages. This process is driven by the recognition of self-antigens and leads to the differentiation into specialized effector subsets, for example, invariant natural killer T (iNKT) cells, mucosal associated invariant T (MAIT) cells, intestinal intraepithelial lymphocytes (iIELs), as well as several γδT cell subsets¹.

Interestingly, recent studies demonstrated that many innate-like T cells, including both γδ and αβT cells, are thymus-resident^2,3. The reason for the accumulation of effector T cells at the site of T cell development, where pathogen encounter is unlikely, remains enigmatic. These cells express a broad range of effector molecules that form a unique class of self-antigens, which are induced during infection alongside foreign antigens. How the immune system differentiates these self-antigens from molecules derived from pathogens remains poorly understood.

All three classes of adaptive lymphocytes contain innate-like populations^4,5, but γδT cells are particularly enriched for these cells⁶. Yet, while ligands for antigen receptors of both innate-like and conventional B cells and αβT cells are well characterized, the principles of antigen recognition by γδT cells, the nature of these antigens, and therefore the functions of γδT cells, remain largely elusive^7,8.

In this thesis, we first dissected the role of thymus-resident innate-like T cells in the induction of tolerance to inflammation-associated autoantigens. We found that minute number of these cells mediated efficient tolerance of CD8T cells to model inflammation-associated autoantigens. Furthermore, we found that expression of an endogenous T cell effector molecule, interferon γ (IFNγ), solely by hematopoietic cells (mainly T/NK/ILCs) was sufficient to mediate efficient tolerance of CD8+ T cells to this cytokine (Paper I).

Secondly, we developed a pipeline for the assessment of the γδTCR specificities, demonstrated that a large fraction of γδT cells recognizes a diverse spectrum of unidentified molecules that do not belong to known classes of γδTCR ligands and identified one such novel ligand – interleukin IL17 receptor A (IL17RA). Further analysis suggested that IL17RA interacts with Vδ7-containing γδTCRs in a superantigen-like manner and is required for the functional maturation of a major subset of Vδ7 γδT cells (Paper II).

Thirdly, in addition to these studies on the cell fate decisions involving innate-like T cells, we also investigated lineage choices made by conventional lymphocytes and elucidated how antigen availability influences the fate of activated B cells during the early immune response (Paper III).

List of scientific papers

I. Yuanyuan You*, Josefine Dunst*, Kewei Ye, Patrick A. Sandoz, Annika Reinhardt, Inga Sandrock, Natalia R. Comet, Rupak Dey Sarkar, Emily Yang, Estelle Duprez, Judith Agudo, Brian D. Brown, Paul J. Utz, Wolfgang Kastenmüller, Carmen Gerlach, Immo Prinz, Björn Önfelt & Taras Kreslavsky. Direct presentation of inflammation-associated self-antigens by thymic innate-like T cells induces elimination of autoreactive CD8+ thymocytes. Nature Immunology. 2024 Aug;25(8):1367-1382. https://doi.org/10.1038/s41590-024-01899-6

II. Kewei Ye, Josefine Dunst, Stefanie Köhler, Anatoly Dubnovitsky, Yuanyuan You, Anja Kramer, Tommy Regen, Ari Waisman, Vivianne Malmström, Jan Kisielow, Thomas Winkler, Thomas Krey, and Taras Kreslavsky. Superantigen-like activation of V87 TCRs by the IL17 receptor A chain drives the differentiation of TH1-like y&T cells. [Manuscript]

III. Vassilis Glaros*, René Rauschmeier*, Artem V Artemov*, Annika Reinhardt*, Sebastian Ols*, Aikaterini Emmanouilidi, Charlotte Gustafsson, Yuanyuan You, Claudio Mirabello, Asa K Björklund, Laurent Perez, Neil P King, Robert Månsson, Davide Angeletti, Karin Loré, Igor Adameyko, Meinrad Busslinger, Taras Kreslavsky. Limited access to antigen drives generation of early B cell memory while restraining the plasmablast response. Immunity. 2021 Sep 14;54(9):2005-2023.e10. https://doi.org/10.1016/j.immuni.2021.08.017

* Equal contribution