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T cell reactivation in acute kidney injury

Applicant Dr. Jan Herter
Subject Area Anaesthesiology
Term from 2016 to 2022
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 318094332
 
Final Report Year 2022

Final Report Abstract

For the first time, our transcriptome analysis revealed genes specific for effector T cell reactivation besides T cell priming and differentiation. Via sorting and transcriptome analysis we observed that the amount of genes uniquely regulated in effector T cell activation is comparable to the amount defining linage differentiation and goes beyond T cell activation per se compared to naïve cell activation. We thus find that on a transcriptome level, effector reactivation is a uniquely defined event. The expression of selected genes from this transcriptome analysis showed similar tendencies in expression in all CD4 + T cell effector subpopulations, although expression strength differed. These results might indicate that reactivation could be a process sharing overlap over the effector subpopulation types. It is particularly interesting that most of the identified genes were not described or characterized in T cell populations before. Clec4e is one identified gene, which was not only significantly upregulated in vitro in all CD4+ T cell subpopulations, but was also significantly upregulated in sorted CD4+ T cells from inflamed kidneys (NTN model) and significantly upregulated in human T H1 cells upon reactivation. To our knowledge, Clec4e was mainly characterized in innate immune cells and there is no study available, which describes the expression of Clec4e on T cells. Furthermore, our results showed that Clec7a was significantly upregulated in vitro in all CD4+ T cell subpopulations, except TH17 cells - although there was a trend towards upregulation. Furthermore, it was significantly upregulated on protein level on sorted CD4 + T cells from inflamed kidneys (NTN) and on Nur77GFP+ CD4+ T cells from inflamed CNS (EAE), although it was not significantly upregulated on human TH1 cells, but results showed a trend towards upregulation. Clec7a is mainly described on innate immune cells, but a recent publication showed that Clec7a expression in CAR T cells leads to significantly higher cytokine secretion and may increase their clinical potential. This study and our findings make Clec7a a possible candidate for immunotherapy. Taken together, our study identified effector reactivation as a transcriptionally distinct process compared to effector differentiation as well as T cell activation. Furthermore, our studies reveal a variety of interesting genes defining this process, however in vivo results have varied significantly in the validation of these genes, indicating the need for further research as the in vivo microenvironment appears to significantly shape this process beyond our idealized in vitro setting.

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