TY  - JOUR
A1  - Dahlhoff, Julia
A1  - Manz, Hannah
A1  - Steinfatt, Tim
A1  - Delgado-Tascon, Julia
A1  - Seebacher, Elena
A1  - Schneider, Theresa
A1  - Wilnit, Amy
A1  - Mokhtari, Zeinab
A1  - Tabares, Paula
A1  - Böckle, David
A1  - Rasche, Leo
A1  - Martin Kortüm, K.
A1  - Lutz, Manfred B.
A1  - Einsele, Hermann
A1  - Brandl, Andreas
A1  - Beilhack, Andreas
T1  - Transient regulatory T-cell targeting triggers immune control of multiple myeloma and prevents disease progression
JF  - Leukemia
N2  - Multiple myeloma remains a largely incurable disease of clonally expanding malignant plasma cells. The bone marrow microenvironment harbors treatment-resistant myeloma cells, which eventually lead to disease relapse in patients. In the bone marrow, CD4\(^{+}\)FoxP3\(^{+}\) regulatory T cells (Tregs) are highly abundant amongst CD4\(^{+}\) T cells providing an immune protective niche for different long-living cell populations, e.g., hematopoietic stem cells. Here, we addressed the functional role of Tregs in multiple myeloma dissemination to bone marrow compartments and disease progression. To investigate the immune regulation of multiple myeloma, we utilized syngeneic immunocompetent murine multiple myeloma models in two different genetic backgrounds. Analyzing the spatial immune architecture of multiple myeloma revealed that the bone marrow Tregs accumulated in the vicinity of malignant plasma cells and displayed an activated phenotype. In vivo Treg depletion prevented multiple myeloma dissemination in both models. Importantly, short-term in vivo depletion of Tregs in mice with established multiple myeloma evoked a potent CD8 T cell- and NK cell-mediated immune response resulting in complete and stable remission. Conclusively, this preclinical in-vivo study suggests that Tregs are an attractive target for the treatment of multiple myeloma.
KW  - Multiple myeloma
KW  - transient regulatory T-cell targeting
KW  - immune control
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-271787
SN  - 1476-5551
VL  - 36
IS  - 3
ER  - 
TY  - JOUR
A1  - Pils, Stefan
A1  - Kopp, Kathrin
A1  - Peterson, Lisa
A1  - Tascon, Julia Delgado
A1  - Nyffenegger-Jann, Naja J.
A1  - Hauck, Christof R.
T1  - The Adaptor Molecule Nck Localizes the WAVE Complex to Promote Actin Polymerization during CEACAM3-Mediated Phagocytosis of Bacteria
JF  - PLoS One
N2  - Background: CEACAM3 is a granulocyte receptor mediating the opsonin-independent recognition and phagocytosis of human-restricted CEACAM-binding bacteria. CEACAM3 function depends on an intracellular immunoreceptor tyrosine-based activation motif (ITAM)-like sequence that is tyrosine phosphorylated by Src family kinases upon receptor engagement. The phosphorylated ITAM-like sequence triggers GTP-loading of Rac by directly associating with the guanine nucleotide exchange factor (GEF) Vav. Rac stimulation in turn is critical for actin cytoskeleton rearrangements that generate lamellipodial protrusions and lead to bacterial uptake. 
Principal Findings: In our present study we provide biochemical and microscopic evidence that the adaptor proteins Nck1 and Nck2, but not CrkL, Grb2 or SLP-76, bind to tyrosine phosphorylated CEACAM3. The association is phosphorylation-dependent and requires the Nck SH2 domain. Overexpression of the isolated Nck1 SH2 domain, RNAi-mediated knock-down of Nck1, or genetic deletion of Nck1 and Nck2 interfere with CEACAM3-mediated bacterial internalization and with the formation of lamellipodial protrusions. Nck is constitutively associated with WAVE2 and directs the actin nucleation promoting WAVE complex to tyrosine phosphorylated CEACAM3. In turn, dominant-negative WAVE2 as well as shRNA-mediated knock-down of WAVE2 or the WAVE-complex component Nap1 reduce internalization of bacteria. 
Conclusions: Our results provide novel mechanistic insight into CEACAM3-initiated phagocytosis. We suggest that the CEACAM3 ITAM-like sequence is optimized to co-ordinate a minimal set of cellular factors needed to efficiently trigger actin-based lamellipodial protrusions and rapid pathogen engulfment.
KW  - activation
KW  - neisseria gonorrhoeae
KW  - human pathogens
KW  - T cell
KW  - signal transduction
KW  - escherichia coli
KW  - epithelial cells
KW  - tyrosine kinase
KW  - receptor
KW  - adhesion
Y1  - 2012
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-131747
VL  - 7
IS  - 3
ER  -