@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{BanasSteublRendersetal.2018,
  author    = {Banas, Bernhard and Steubl, Dominik and Renders, Lutz and Chittka, Dominik and Banas, Miriam C. and Wekerle, Thomas and Koch, Martina and Witzke, Oliver and M{\"u}hlfeld, Anja and Sommerer, Claudia and Habicht, Antje and Hugo, Christian and H{\"u}nig, Thomas and Lindemann, Monika and Schmidt, Traudel and Rascle, Anne and Barabas, Sascha and Deml, Ludwig and Wagner, Ralf and Kr{\"a}mer, Bernhard K. and Kr{\"u}ger, Bernd},
  title     = {Clinical validation of a novel enzyme-linked immunosorbent spot assay-based in vitro diagnostic assay to monitor cytomegalovirus-specific cell-mediated immunity in kidney transplant recipients: a multicenter, longitudinal, prospective, observational study},
  series = {Transplant International},
  volume    = {31},
  journal   = {Transplant International},
  doi       = {10.1111/tri.13110},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-221468},
  pages     = {436-450},
  year      = {2018},
  abstract  = {Impaired cytomegalovirus (CMV)-specific cell-mediated immunity (CMV-CMI) is a major cause of CMV reactivation and associated complications in solid-organ transplantation. Reliably assessing CMV-CMI is desirable to individually adjust antiviral and immunosuppressive therapy. This study aimed to evaluate the suitability of T-Track® CMV, a novel IFN-γ ELISpot assay based on the stimulation of peripheral blood mononuclear cells with pp65 and IE-I CMV proteins, to monitor CMV-CMI following kidney transplantation. A prospective longitudinal multicenter study was conducted in 86 intermediate-risk renal transplant recipients. CMV-CMI, CMV viral load, and clinical complications were monitored over 6 months post-transplantation. Ninety-five percent and 88-92\% ELISpot assays were positive pre- and post-transplantation, respectively. CMV-specific response was reduced following immunosuppressive treatment and increased in patients with graft rejection, indicating the ability of the ELISpot assay to monitor patients' immunosuppressive state. Interestingly, median pp65-specific response was ninefold higher in patients with self-clearing viral load compared to antivirally treated patients prior to first viral load detection (P < 0.001), suggesting that reactivity to pp65 represents a potential immunocompetence marker. Altogether, T-Track® CMV is a highly sensitive IFN-γ ELISpot assay, suitable for the immunomonitoring of CMV-seropositive renal transplant recipients, and with a potential use for the risk assessment of CMV-related clinical complications (ClinicalTrials.gov Identifier: NCT02083042).},
  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}
}