TY  - JOUR
A1  - Langenhorst, Daniela
A1  - Tabares, Paula
A1  - Gulde, Tobias
A1  - Becklund, Bryan R.
A1  - Berr, Susanne
A1  - Surh, Charles D.
A1  - Beyersdorf, Niklas
A1  - Hünig, Thomas
T1  - Self-recognition sensitizes mouse and human regulatory T cells to low-dose CD28 superagonist stimulation
JF  - Frontiers in Immunology
N2  - In rodents, low doses of CD28-specific superagonistic monoclonal antibodies (CD28 superagonists, CD28SA) selectively activate regulatory T cells (Treg). This observation has recently been extended to humans, suggesting an option for the treatment of autoimmune and inflammatory diseases. However, a mechanistic explanation for this phenomenon is still lacking. Given that CD28SA amplify T cell receptor (TCR) signals, we tested the hypothesis that the weak tonic TCR signals received by conventional CD4\(^{+}\) T cells (Tconv) in the absence of cognate antigen require more CD28 signaling input for full activation than the stronger TCR signals received by self-reactive Treg. We report that in vitro, the response of mouse Treg and Tconv to CD28SA strongly depends on MHC class II expression by antigen-presenting cells. To separate the effect of tonic TCR signals from self-peptide recognition, we compared the response of wild-type Treg and Tconv to low and high CD28SA doses upon transfer into wild-type or H-2M knockout mice, which lack a self-peptide repertoire. We found that the superior response of Treg to low CD28SA doses was lost in the absence of self-peptide presentation. We also tested if potentially pathogenic autoreactive Tconv would benefit from self-recognition-induced sensitivity to CD28SA stimulation by transferring TCR transgenic OVA-specific Tconv into OVA-expressing mice and found that low-dose CD28SA application inhibited, rather than supported, their expansion, presumably due to the massive concomitant activation of Treg. Finally, we report that also in the in vitro response of human peripheral blood mononuclear cells to CD28SA, HLA II blockade interferes with the expansion of Treg by low-dose CD28SA stimulation. These results provide a rational basis for the further development of low-dose CD28SA therapy for the improvement of Treg activity.
KW  - D665
KW  - regulatory T cells
KW  - self-reactivity
KW  - autoimmunity
KW  - CD28 superagonists
KW  - TGN1412
KW  - TAB08
Y1  - 2018
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-159387
VL  - 8
IS  - 1985
ER  - 
TY  - JOUR
A1  - Medler, Juliane
A1  - Nelke, Johannes
A1  - Weisenberger, Daniela
A1  - Steinfatt, Tim
A1  - Rothaug, Moritz
A1  - Berr, Susanne
A1  - Hünig, Thomas
A1  - Beilhack, Andreas
A1  - Wajant, Harald
T1  - TNFRSF receptor-specific antibody fusion proteins with targeting controlled FcγR-independent agonistic activity
JF  - Cell Death & Disease
N2  - Antibodies specific for TNFRSF receptors that bind soluble ligands without getting properly activated generally act as strong agonists upon FcγR binding. Systematic analyses revealed that the FcγR dependency of such antibodies to act as potent agonists is largely independent from isotype, FcγR type, and of the epitope recognized. This suggests that the sole cellular attachment, achieved by Fc domain-FcγR interaction, dominantly determines the agonistic activity of antibodies recognizing TNFRSF receptors poorly responsive to soluble ligands. In accordance with this hypothesis, we demonstrated that antibody fusion proteins harboring domains allowing FcγR-independent cell surface anchoring also act as strong agonist provided they have access to their target. This finding defines a general possibility to generate anti-TNFRSF receptor antibodies with FcγR-independent agonism. Moreover, anti-TNFRSF receptor antibody fusion proteins with an anchoring domain promise superior applicability to conventional systemically active agonists when an anchoring target with localized disease associated expression can be addressed.
KW  - biologics
KW  - proteins
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-223948
VL  - 10
ER  -