The role of Interferon Regulatory Factor 4 in the regulation of T-cell memory
Final Report Abstract
The project aimed to analyze the function of Interferon Regulatory Factor 4 (IRF4) in memory T cells. IRF4 is expressed following T cell stimulation and is essential for the activation and differentiation of CD4+ and CD8+ T cells into effector T cells. In order to study the role of IRF4 in memory T cells, we created a mouse model that allowed us to inactivate the Irf4 gene after T cell priming and memory T cell formation. We then combined this model with infection models to analyze the function of IRF4 in memory CD4+ and CD8+ T cells, as well as in regulatory T (Treg) cells. Upon Irf4 inactivation, memory CD8+ T cells exhibited phenotypic changes and impaired expansion and reduced effector functions during a secondary infection. While CD8+ memory T cells in general did not decline, Irf4 inactivation caused a reduction in tissue-resident memory T cells, which expressed higher levels of IRF4. Following infection with the intestinal nematode Strongyloides ratti and the bacterial pathogen Citrobacter rodentium, Irf4-deficient mice failed to mount Th2 and Th17 cell responses, respectively. There was also reduced accumulation of CD4+ T cells in the intestinal tract of Irf4- deficient mice due, at least in part, to impaired expression of intestinal homing receptors. The formation and accumulation of Th2 and Th17 cells in the intestine was impaired in Irf4 heterozygous mutant mice, indicating a strong dose dependency for IRF4 in these processes. Deletion of Irf4 alleles following infection reduced the CD4+ T cell population in the colon; however, it did not diminish the number of Th2 and Th17 T cells in other tissues. This suggests that IRF4 is not essential for maintaining the differentiation state of memory T cells. In Treg cells, inactivation of Irf4 alleles impaired the differentiation of effector Treg cells and decreased Treg cell homeostasis. Once again, we observed a dose-dependent effect, with the inactivation of just one Irf4 allele causing a loss of effector Treg cells. Analysis of gene loci revealed altered accessibility of several genes in Treg cells with inactivated Irf4 alleles. In the FoxP3 gene locus, which is essential for Treg cell differentiation and function, regions with altered accessibility included the promoter and the CNS2 element. Both of these are required for the stability of FoxP3 expression in peripheral Treg cells. In summary, our results demonstrate that IRF4 controls the differentiation and function of all analyzed T cell subsets in a dose-dependent manner. In memory T cells, IRF4 is required for the maintenance of several subsets, including tissue-resident T cells and Treg cells, and is essential for their function upon reactivation.
Publications
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Arc/Arg3.1 defines dendritic cells and Langerhans cells with superior migratory ability independent of phenotype and ontogeny in mice. European Journal of Immunology, 49(5), 724-736.
Tintelnot, Joseph; Ufer, Friederike; Engler, Jan Broder; Winkler, Hana; Lücke, Karsten; Mittrücker, Hans‐Willi & Friese, Manuel A.
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Interferon regulatory factor 4 controls effector functions of CD8 + memory T cells. Proceedings of the National Academy of Sciences, 118(16).
Harberts, Aenne; Schmidt, Constantin; Schmid, Joanna; Reimers, Daniel; Koch-Nolte, Friedrich; Mittrücker, Hans-Willi & Raczkowski, Friederike
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IRF4 is required for migration of CD4+ T cells to the intestine but not for Th2 and Th17 cell maintenance. Frontiers in Immunology, 14.
Schmidt, Constantin; Harberts, Aenne; Reimers, Daniel; Bertram, Tabea; Voß, Leonie Caroline; Schmid, Joanna; Lory, Niels Christian; Spohn, Michael; Koch-Nolte, Friedrich; Huber, Samuel; Raczkowski, Friederike; Breloer, Minka & Mittrücker, Hans-Willi
