Seminar: Adriaan Bins

Dermal DNA vaccines encoding secreted antigens favor solicitation of CD4+ T-cell help and optimal cytotoxic T-cell responsiveness

Date:
14 September 2017 15:00 hrs. - 16:00 hrs.
Location:
Location see remarks
Title:
Dermal DNA vaccines encoding secreted antigens favor solicitation of CD4+ T-cell help and optimal cytotoxic T-cell responsiveness
Speaker(s):

Adriaan D. Bins, Dept. of Internal medicine, AMC Amsterdam

Host(s):

Martijn Verdoes, Dept. of Tumor Immunology, RIMLS

14-09-2017 15:00:0014-09-2017 16:00:00Europe/AmsterdamDermal DNA vaccines encoding secreted antigens favor solicitation of CD4+ T-cell help and optimal cytotoxic T-cell responsiveness Location see remarksRimlsrimls@radboudumc.nl

Remarks / more information:

Location: Knowledge square 5th floor RIMLS building, route 278

Download flyer here.

Therapeutic vaccination aims to elicit an effective cytotoxic T lymphocyte (CTL) response. Inclusion of MHC Class II epitopes next to MHC Class I epitopes has improved the generation of CTL responses by virtue of CD4+ T-cell help, but therapeutic success is still absent. To understand potential mechanisms that limit CTL responsiveness, we have studied antigen routing from the skin to draining lymph nodes (dLNs) by a novel approach using MHC Class I and Class II ovalbumin (OVA) epitopes conjugated to stable ZsGreen fluorescent protein. Cytosolic, membrane-bound, nuclear and secreted versions of the same protein were expressed in keratinocytes by DNA “tattoo” vaccination. Antigen was delivered to B cells in dLNs, indicating passive drainage from the skin. B cells proved irrelevant for CTL priming. The measure of DC loading with the different antigen formulations did not correlate with the magnitude of the CTL response. The antigen was mainly detected in migratory DCs in the dLN, but these were incapable of CTL priming, unless they were activated in vitro. Thus, the deficient activation status of antigen-loaded DCs proved to be the bottleneck in CTL priming. Accordingly, CTL priming to all antigen formulations relied on CD4+ T-cell help. The secreted antigen maximally solicited CD4+ T-cell help and optimally primed CTLs. The suboptimal response to cytosolic, nuclear or membrane-bound antigens was improved by engaging the costimulatory receptor CD27 as a substitute for CD4+ T-cell help. Thus, therapeutic vaccination can be improved by securing CD4+ T-cell help, either by appropriate formulation of the antigen or by CD27 agonism.

 

Key publications

  • Lankelma JM, Wagemakers A, Birnie E, Haak BW, Trentelman JJA, Weehuizen TAF, Ersöz J, Roelofs JJTH, Hovius JW, Wiersinga WJ, Bins AD. 2017. Rapid DNA vaccination against Burkholderia pseudomallei flagellin by tattoo or intranasal application. Virulence 4: 1-12. 
  • Headley MB, A Bins, A Nip, EW Roberts, MR Looney, A Gerard, MF Krummel. 2016. Visualization of Immediate Immune Responses to Pioneer Metastatic Cells in the Lung. Nature 531: 513–17.
  • Wagemakers A, LMK Mason, A Oei, B de Wever, T van der Poll,  JWR Hovius, AD Bins. 2014. Rapid outer-surface protein C DNA tattoo vaccination protects against Borrelia afzelii infection. Gene Ther. 21: 1051–57.
  • Bins AD, A. Jorritsma, MC Wolkers, C-F Hung, T-C Wu, TNM Schumacher, JBAG Haanen. 2005. A rapid and potent DNA vaccination strategy defined by in vivo monitoring of antigen expression. Nature Medicine 11: 899–904.

 



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