Antigen kinetics determines immune reactivity

doi:10.1073/pnas.0706296105

Antigen kinetics determines immune reactivity

*Unit Experimental Immunotherapy, Department of Dermatology, University Hospital Zurich, Gloriastrasse 31, CH-8091 Zurich, Switzerland;
^†MannKind Corporation, 28903 North Avenue Paine, Valencia, CA 91355;
^‡Cytos Biotechnology, Wagistrasse 25, CH-8952 Schlieren, Switzerland;
^§Institute of Experimental Immunology, University Hospital Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland;
^¶Clinical Trials Center, University Hospital Zurich, Gloriastrasse 31, CH-8091 Zurich, Switzerland;
^‖Department of Gastroenterology and Hepatology, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland; and
**Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Raemistrasse 100, CH-8091 Zurich, Switzerland

Edited by Tak Wah Mak, University of Toronto, Toronto, ON, Canada, and approved January 15, 2008 (received for review July 5, 2007)

Abstract

A current paradigm in immunology is that the strength of T cell responses is governed by antigen dose, localization, and costimulatory signals. This study investigates the influence of antigen kinetics on CD8 T cell responses in mice. A fixed cumulative antigen dose was administered by different schedules to produce distinct dose-kinetics. Antigenic stimulation increasing exponentially over days was a stronger stimulus for CD8 T cells and antiviral immunity than a single dose or multiple dosing with daily equal doses. The same was observed for dendritic cell vaccination, with regard to T cell and anti-tumor responses, and for T cells stimulated in vitro. In conclusion, stimulation kinetics per se was shown to be a separate parameter of immunogenicity. These findings warrant a revision of current immunization models and have implications for vaccine development and immunotherapy.

Footnotes

^††To whom correspondence should be addressed. E-mail: thomas.kuendig{at}usz.ch
Author contributions: P.J. and T.S. contributed equally to this work; P.J., T.S., L.R., K.A.S., G.S., B.M., T.G., R.F.S., A.B., and T.M.K. designed research; P.J., T.S., L.R., Z.Q., A.D.-S., V.M., and K.S.L. performed research; K.A.S. and A.B. contributed new reagents/analytic tools; P.J., T.S., L.R., Z.Q., A.D.-S., V.M., K.S.L., and T.M.K. analyzed data; and P.J., T.S., L.R., K.A.S., R.F.S., A.B., and T.M.K. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0706296105/DC1.