TY  - JOUR
A1  - Cochain, Clement
A1  - Chaudhari, Sweena M.
A1  - Koch, Miriam
A1  - Wiendl, Heinz
A1  - Eckstein, Hans-Henning
A1  - Zernecke, Alma
T1  - Programmed Cell Death-1 Deficiency Exacerbates T Cell Activation and Atherogenesis despite Expansion of Regulatory T Cells in Atherosclerosis-Prone Mice
JF  - PLoS ONE
N2  - T cell activation represents a double-edged sword in atherogenesis, as it promotes both pro-inflammatory T cell activation and atheroprotective Foxp3(+) regulatory T cell (Treg) responses. Here, we investigated the role of the co-inhibitory receptor programmed cell death-1 (PD-1) in T cell activation and CD4(+) T cell polarization towards pro-atherogenic or atheroprotective responses in mice. Mice deficient for both low density lipoprotein receptor and PD-1 (Ldlr(-/-)Pd1(-/-)) displayed striking increases in systemic CD4(+) and CD8(+) T cell activation after 9 weeks of high fat diet feeding, associated with an expansion of both pro-atherogenic IFNγ-secreting T helper 1 cells and atheroprotective Foxp3+ Tregs. Importantly, PD-1 deficiency did not affect Treg suppressive function in vitro. Notably, PD-1 deficiency exacerbated atherosclerotic lesion growth and entailed a massive infiltration of T cells in atherosclerotic lesions. In addition, aggravated hypercholesterolemia was observed in Ldlr(-/-)Pd1(-/-) mice. In conclusion, we here demonstrate that although disruption of PD-1 signaling enhances both pro- and anti-atherogenic T cell responses in Ldlr(-/-) mice, pro-inflammatory T cell activation prevails and enhances dyslipidemia, vascular inflammation and atherosclerosis.
KW  - nutritional deficiencies
KW  - atherosclerosis
KW  - spleen
KW  - aorta
KW  - diet
KW  - cytotoxic T cells
KW  - regulatory T cells
KW  - T cells
Y1  - 2014
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-119823
SN  - 1932-6203
VL  - 9
IS  - 4
ER  - 
TY  - JOUR
A1  - Rasche, Leo
A1  - Kumar, Manoj
A1  - Gershner, Grant
A1  - Samant, Rohan
A1  - Van Hemert, Rudy
A1  - Heidemeier, Anke
A1  - Lapa, Constantin
A1  - Bley, Thorsten
A1  - Buck, Andreas
A1  - McDonald, James
A1  - Hillengass, Jens
A1  - Epstein, Joshua
A1  - Thanendrarajan, Sharmilan
A1  - Schinke, Carolina
A1  - van Rhee, Frits
A1  - Zangari, Maurizio
A1  - Barlogie, Bart
A1  - Davies, Faith E.
A1  - Morgan, Gareth J.
A1  - Weinhold, Niels
T1  - Lack of Spleen Signal on Diffusion Weighted MRI is associated with High Tumor Burden and Poor Prognosis in Multiple Myeloma: A Link to Extramedullary Hematopoiesis?
JF  - Theranostics
N2  - Due to the low frequency of abnormalities affecting the spleen, this organ is often overlooked during radiological examinations. Here, we report on the unexpected finding, that the spleen signal on diffusion-weighted MRI (DW-MRI) is associated with clinical parameters in patients with plasma cell dyscrasias. Methods: We investigated the spleen signal on DW-MRI together with clinical and molecular parameters in 295 transplant-eligible newly diagnosed Multiple Myeloma (NDMM) patients and in 72 cases with monoclonal gammopathy of undetermined significance (MGUS). Results: Usually, the spleen is the abdominal organ with the highest intensities on DW-MRI. Yet, significant signal loss on DW-MRI images was seen in 71 of 295 (24%) NDMM patients. This phenomenon was associated with the level of bone marrow plasmacytosis (P=1x10(-10)) and International Staging System 3 (P=0.0001) but not with gain(1q), and del(17p) or plasma cell gene signatures. The signal was preserved in 72 individuals with monoclonal gammopathy of undetermined significance and generally re-appeared in MM patients responding to treatment, suggesting that lack of signal reflects increased tumor burden. While absence of spleen signal in MM patients with high risk disease defined a subgroup with very poor outcome, re-appearance of the spleen signal after autologous stem cell transplantation was seen in patients with improved outcome. Our preliminary observation suggests that extramedullary hematopoiesis in the spleen is a factor that modifies the DW-MRI signal of this organ. Conclusions: The DW-MRI spleen signal is a promising marker for tumor load and provides prognostic information in MM.
KW  - multiple myeloma
KW  - diffusion weighted mri
KW  - spleen
KW  - tumor burden
KW  - high risk
KW  - extramedullary hematopoiesis
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-224982
VL  - 9
IS  - 16
ER  - 
TY  - JOUR
A1  - Eckert, Ina N.
A1  - Ribechini, Eliana
A1  - Jarick, Katja J.
A1  - Strozniak, Sandra
A1  - Potter, Sarah J.
A1  - Beilhack, Andreas
A1  - Lutz, Manfred B.
T1  - VLA-1 Binding to Collagen IV Controls Effector T Cell Suppression by Myeloid-Derived Suppressor Cells in the Splenic Red Pulp
JF  - Frontiers in Immunology
N2  - Myeloid-derived suppressor cells (MDSCs) represent a major population controlling T cell immune responses. However, little is known about their molecular requirements for homing and T cell interaction to mediate suppression. Here, we investigated the functional role of the homing and collagen IV receptor VLA-1 (α1β1-integrin) on in vitro GM-CSF generated murine MDSCs from wild-type (WT) and CD49a/α1-integrin (Itga1\(^{−/−}\)) gene-deficient mice. Here, we found that effector (Teff) but not naive (Tn) CD4\(^+\) T cells express VLA-1 and monocytes further up-regulated their expression after culture in GM-CSF when they differentiated into the monocytic subset of resting MDSCs (R-MDSCs). Subsequent activation of R-MDSCs by LPS+IFN-γ (A-MDSCs) showed increased in vitro suppressor potential, which was independent of VLA-1. Surprisingly, VLA-1 deficiency did not influence A-MDSC motility or migration on collagen IV in vitro. However, interaction times of Itga1\(^{−/−}\) A-MDSCs with Teff were shorter than with WT A-MDSCs on collagen IV but not on fibronectin substrate in vitro. After injection, A-MDSCs homed to the splenic red pulp where they co-localized with Teff and showed immediate suppression already after 6 h as shown by inhibition of T cell proliferation and induction of apoptosis. Injection of A-MDSCs from Itga1\(^{−/−}\) mice showed equivalent homing into the spleen but a reduced suppressive effect. Interaction studies of A-MDSCs with Teff in the subcapsular red pulp with intravital two-photon microscopy revealed also here that MDSC motility and migration parameters were not altered by VLA-1 deficiency, but the interaction times with Teff were reduced. Together, our data point to a new role of VLA-1 adhesion to collagen IV as a prerequisite for extended contact times with Teff required for suppression.
KW  - myeloid-derived suppressor cells (MDSCs)
KW  - T cells
KW  - VLA-1
KW  - homing
KW  - spleen
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-222671
SN  - 1664-3224
VL  - 11
ER  -