Deciphering endogenous and environmental factors impacting on development and function of iNKT cell subsets
Final Report Abstract
Serving as a bridge between innate and adaptive immunity, innate-like T cells are a heterogeneous group of T cells emerging as an appealing target in immune therapies. Classified in this group, invariant natural killer T (iNKT) cells represent innate-like T cells capable of swift responses to cognate antigens or respective cytokine stimuli. Akin to conventional T cells, iNKT cells develop in the thymus, however both cell fractions follow different pathways for positive selection where conventional T cells are being selected by thymic epithelial cells and innate-like T cells are selected by double positive (DP) thymocytes. Furthermore, in contrast to conventional T cells which are positively selected on peptides presented by classical major histocompatibility complex (MHC) molecules, iNKT cells are selected on lipid antigens presented by CD1d non-classical MHC molecule limiting their T cell receptor (TCR) repertoire. In this study we have generated a novel inducible mouse model allowing cell-subset specific upregulation of classical major histocompatibility complex MHC I molecules. Utilizing this model, we upregulated the expression of classical MHC I molecules on double positive (DP) stage thymocytes which led to expansion of peptide-specific PLZF+ innate-like (PIL) T cells. Moreover, were able to show that PIL T cells development was CD1d independent but required triggering of signaling lymphocyte activation molecule family (SLAMF) receptors. We further showed that PIL T cells developing in this mouse model display similar functional and phenotypic characteristics as iNKT cells. In addition, we could show that CD4 coreceptor signaling is crucial for IL-4 production under steady-state by this cell subset. Finally, we provided evidence for the existence of a narrow niche in the thymus supporting innatelike T cell development and that iNKT and PIL T cells compete for such a niche.
Publications
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Impact of Aging on the Phenotype of Invariant Natural Killer T Cells in Mouse Thymus. Front Immunol. 2020 Oct 30;11:575764
Papadogianni G, Ravens I, Dittrich-Breiholz O, Bernhardt G, Georgiev H
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Recent advances in iNKT cell development. F1000Res. 2020;9:F1000 Faculty Rev-127
Hogquist K, Georgiev H
