TY  - JOUR
A1  - Giampaolo, Sabrina
A1  - Wójcik, Gabriela
A1  - Serfling, Edgar
A1  - Patra, Amiya K.
T1  - Interleukin-2-regulatory T cell axis critically regulates maintenance of hematopoietic stem cells
JF  - Oncotarget
N2  - The role of IL-2 in HSC maintenance is unknown. Here we show that Il2\(^{−/-}\) mice develop severe anomalies in HSC maintenance leading to defective hematopoiesis. Whereas, lack of IL-2 signaling was detrimental for lympho- and erythropoiesis, myelopoiesis was enhanced in Il2\(^{−/-}\) mice. Investigation of the underlying mechanisms of dysregulated hematopoiesis in Il2\(^{−/-}\) mice shows that the IL-2-T\(_{reg}\) cell axis is indispensable for HSC maintenance and normal hematopoiesis. Lack of T\(_{reg}\) activity resulted in increased IFN-γ production by activated T cells and an expansion of the HSCs in the bone marrow (BM). Though, restoring T\(_{reg}\) population successfully rescued HSC maintenance in Il2\(^{-/-}\) mice, preventing IFN-γ activity could do the same even in the absence of T\(_{reg}\) cells. Our study suggests that equilibrium in IL-2 and IFN-γ activity is critical for steady state hematopoiesis, and in clinical conditions of BM failure, IL-2 or anti-IFN-γ treatment might help to restore hematopoiesis.
KW  - immunity
KW  - hematopoietic stem cells
KW  - IL-2
KW  - treg cells
KW  - IL-10
KW  - IFN-γ
KW  - immunology and microbiology section
KW  - immune response
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170947
VL  - 8
IS  - 18
ER  - 
TY  - JOUR
A1  - Heuser, Christoph
A1  - Gotot, Janine
A1  - Piotrowski, Eveline Christina
A1  - Philipp, Marie-Sophie
A1  - Courrèges, Christina Johanna Felicia
A1  - Otte, Martin Sylvester
A1  - Guo, Linlin
A1  - Schmid-Burgk, Jonathan Leo
A1  - Hornung, Veit
A1  - Heine, Annkristin
A1  - Knolle, Percy Alexander
A1  - Garbi, Natalio
A1  - Serfling, Edgar
A1  - Evaristo, César
A1  - Thaiss, Friedrich
A1  - Kurts, Christian
T1  - Prolonged IKK\(\beta\) Inhibition Improves Ongoing CTL Antitumor Responses by Incapacitating Regulatory T Cells
JF  - Cell Reports
N2  - Regulatory T cells (Tregs) prevent autoimmunity but limit antitumor immunity. The canonical NF-\(\kappa\)B signaling pathway both activates immunity and promotes thymic Treg development. Here, we report that mature Tregs continue to require NF-\(\kappa\)B signaling through I\(\kappa\)B-kinase \(\beta\) (IKK\(\beta\)) after thymic egress. Mice lacking IKK\(\beta\) in mature Tregs developed scurfy-like immunopathology due to death of peripheral FoxP3\(^+\) Tregs. Also, pharmacological IKK\(\beta\) inhibition reduced Treg numbers in the circulation by ~50% and downregulated FoxP3 and CD25 expression and STAT5 phosphorylation. In contrast, activated cytotoxic T lymphocytes (CTLs) were resistant to IKK\(\beta\) inhibition because other pathways, in particular nuclear factor of activated T cells (NFATc1) signaling, sustained their survival and expansion. In a melanoma mouse model, IKK\(\beta\) inhibition after CTL cross-priming improved the antitumor response and delayed tumor growth. In conclusion, prolonged IKK\(\beta\) inhibition decimates circulating Tregs and improves CTL responses when commenced after tumor vaccination, indicating that IKK\(\beta\) represents a druggable checkpoint.
KW  - medicine
KW  - regulatory T cells
KW  - NF-\(\kappa\)B pathway
KW  - tumor vaccination
KW  - checkpoint inhibition
KW  - cytotoxic T cells
KW  - cross-priming
KW  - apoptosis
KW  - tumor immunology
KW  - melanoma
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-173643
VL  - 21
IS  - 3
ER  - 
TY  - JOUR
A1  - Klein-Hessling, Stefan
A1  - Muhammad, Khalid
A1  - Klein, Matthias
A1  - Pusch, Tobias
A1  - Rudolf, Ronald
A1  - Flöter, Jessica
A1  - Qureischi, Musga
A1  - Beilhack, Andreas
A1  - Vaeth, Martin
A1  - Kummerow, Carsten
A1  - Backes, Christian
A1  - Schoppmeyer, Rouven
A1  - Hahn, Ulrike
A1  - Hoth, Markus
A1  - Bopp, Tobias
A1  - Berberich-Siebelt, Friederike
A1  - Patra, Amiya
A1  - Avots, Andris
A1  - Müller, Nora
A1  - Schulze, Almut
A1  - Serfling, Edgar
T1  - NFATc1 controls the cytotoxicity of CD8\(^{+}\) T cells
JF  - Nature Communications
N2  - Cytotoxic T lymphocytes are effector CD8\(^{+}\) T cells that eradicate infected and malignant cells. Here we show that the transcription factor NFATc1 controls the cytotoxicity of mouse cytotoxic T lymphocytes. Activation of Nfatc1\(^{-/-}\) cytotoxic T lymphocytes showed a defective cytoskeleton organization and recruitment of cytosolic organelles to immunological synapses. These cells have reduced cytotoxicity against tumor cells, and mice with NFATc1-deficient T cells are defective in controlling Listeria infection. Transcriptome analysis shows diminished RNA levels of numerous genes in Nfatc1\(^{-/-}\) CD8\(^{+}\) T cells, including Tbx21, Gzmb and genes encoding cytokines and chemokines, and genes controlling glycolysis. Nfatc1\(^{-/-}\), but not Nfatc2\(^{-/-}\) CD8\(^{+}\) T cells have an impaired metabolic switch to glycolysis, which can be restored by IL-2. Genome-wide ChIP-seq shows that NFATc1 binds many genes that control cytotoxic T lymphocyte activity. Together these data indicate that NFATc1 is an important regulator of cytotoxic T lymphocyte effector functions.
KW  - cytotoxic T cells
KW  - lymphocyte activation
KW  - signal transduction
KW  - gene regulation
KW  - immune cells
KW  - NFATc1
Y1  - 2017
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-170353
VL  - 8
IS  - 511
ER  -