@article{LangenhorstTabaresGuldeetal.2018,
  author    = {Langenhorst, Daniela and Tabares, Paula and Gulde, Tobias and Becklund, Bryan R. and Berr, Susanne and Surh, Charles D. and Beyersdorf, Niklas and H{\"u}nig, Thomas},
  title     = {Self-recognition sensitizes mouse and human regulatory T cells to low-dose CD28 superagonist stimulation},
  series = {Frontiers in Immunology},
  volume    = {8},
  journal   = {Frontiers in Immunology},
  number    = {1985},
  doi       = {10.3389/fimmu.2017.01985},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-159387},
  year      = {2018},
  abstract  = {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.},
  language  = {en}
}
@article{LangenhorstHaackGoebetal.2018,
  author    = {Langenhorst, Daniela and Haack, Stephanie and G{\"o}b, Selina and Uri, Anna and L{\"u}hder, Fred and Vanhove, Bernhard and H{\"u}nig, Thomas and Beyersdorf, Niklas},
  title     = {CD28 costimulation of T helper 1 cells enhances cytokine release in vivo},
  series = {Frontiers in Immunology},
  volume    = {9},
  journal   = {Frontiers in Immunology},
  number    = {1060},
  doi       = {10.3389/fimmu.2018.01060},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-176726},
  year      = {2018},
  abstract  = {Compared to naive T cells, differentiated T cells are thought to be less dependent on CD28 costimulation for full activation. To revisit the role of CD28 costimulation in mouse T cell recall responses, we adoptively transferred in vitro generated OT-II T helper (Th) 1 cells into C57BL/6 mice (Thy1.2\(^{+}\)) and then either blocked CD28-ligand interactions with Fab fragments of the anti-CD28 monoclonal antibody (mAb) E18 or deleted CD28 expression using inducible CD28 knock-out OT-II mice as T cell donors. After injection of ovalbumin protein in adjuvant into the recipient mice we observed that systemic interferon (IFN)γ release strongly depended on CD28 costimulation of the Th1 cells, while secondary clonal expansion was not reduced in the absence of CD28 costimulation. For human memory CD4\(^{+}\) T cell responses we also noted that cytokine release was reduced upon inhibition of CD28 costimulation. Together, our data highlight the so far underestimated role of CD28 costimulation for the reactivation of fully differentiated CD4\(^{+}\) T cells.},
  language  = {en}
}
@article{LangenhorstGogishviliRibechinietal.2012,
  author    = {Langenhorst, Daniela and Gogishvili, Tea and Ribechini, Eliana and Kneitz, Susanne and McPherson, Kirsty and Lutz, Manfred B. and H{\"u}nig, Thomas},
  title     = {Sequential induction of effector function, tissue migration and cell death during polyclonal activation of mouse regulatory T-cells},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-76009},
  year      = {2012},
  abstract  = {The ability of CD4+Foxp3+ regulatory T-cells (Treg) to produce interleukin (IL)-10 is important for the limitation of inflammation at environmental interfaces like colon or lung. Under steady state conditions, however, few Tregs produce IL-10 ex vivo. To investigate the origin and fate of IL-10 producing Tregs we used a superagonistic mouse anti-mouse CD28 mAb (CD28SA) for polyclonal in vivo stimulation of Tregs, which not only led to their numeric expansion but also to a dramatic increase in IL-10 production. IL-10 secreting Tregs strongly upregulated surface receptors associated with suppressive function as compared to non-producing Tregs. Furthermore, polyclonally expanding Tregs shifted their migration receptor pattern after activation from a CCR7+CCR52 lymph node-seeking to a CCR72CCR5+ inflammationseeking phenotype, explaining the preferential recruitment of IL-10 producers to sites of ongoing immune responses. Finally, we observed that IL-10 producing Tregs from CD28SA stimulated mice were more apoptosis-prone in vitro than their IL-10 negative counterparts. These findings support a model where prolonged activation of Tregs results in terminal differentiation towards an IL-10 producing effector phenotype associated with a limited lifespan, implicating built-in termination of immunosuppression.},
  subject      = {Medizin},
  language  = {en}
}
@article{HaackBaikerSchlegeletal.2021,
  author    = {Haack, Stephanie and Baiker, Sarah and Schlegel, Jan and Sauer, Markus and Sparwasser, Tim and Langenhorst, Daniela and Beyersdorf, Niklas},
  title     = {Superagonistic CD28 stimulation induces IFN-γ release from mouse T helper 1 cells in vitro and in vivo},
  series = {European Journal of Immunology},
  volume    = {51},
  journal   = {European Journal of Immunology},
  number    = {3},
  doi       = {10.1002/eji.202048803},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-239028},
  pages     = {738 -- 741},
  year      = {2021},
  abstract  = {Like human Th1 cells, mouse Th1 cells also secrete IFN-γ upon stimulation with a superagonistic anti-CD28 monoclonal antibody (CD28-SA). Crosslinking of the CD28-SA via FcR and CD40-CD40L interactions greatly increased IFN-γ release. Our data stress the utility of the mouse as a model organism for immune responses in humans.},
  language  = {en}
}