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  • Original Article
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Immunology

Functional characterization of Foxp3-specific spontaneous immune responses

Abstract

Tumor-infiltrating CD4+CD25+ regulatory T cells (Tregs) are associated with an impaired prognosis in several cancers. The transcription factor forkhead box P3 (Foxp3) is generally expressed in Tregs. Here, we identify and characterize spontaneous cytotoxic immune responses to Foxp3-expressing cells in peripheral blood of healthy volunteers and cancer patients. These immune responses were directed against a HLA-A2-restricted peptide epitope derived from Foxp3. Foxp3-reactive T cells were characterized as cytotoxic CD8+ T cells. These cells recognized dendritic cells incubated with recombinant Foxp3 protein indicating that this protein was indeed internalized, processed and cross-presented in the context of HLA-A2. More importantly, however, Foxp3-specific T cells were able to specifically recognize Tregs. Similarly, Foxp3+ malignant T cells established from a Cutaneous T-cell lymphomas (CTCL) patient were readily killed by the Foxp3-specific cytotoxic T lymphocytes. The spontaneous presence of Foxp3-specific cytotoxic T-cell responses suggest a general role of such T cells in the complex network of immune regulation as such responses may eliminate Tregs, that is, suppression of the suppressors. Consequently, induction of Foxp3-specific cytotoxic T-cell responses appears as an attractive tool to boost spontaneous or therapeutically provoked immune responses, for example, for the therapy of cancer.

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Acknowledgements

We thank M Jonassen and T Seremet for their excellent technical assistance. We thank P T Straten for scientific discussions. The study was supported by the Herlev Hospital, the Novo Nordisk Foundation, the Lundbeck foundation, the Danish Cancer Society and the Danish Medical Research Council. The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

Author contributions

Stine Kiaer Larsen performed the research, collected the data and edited the manuscript. S Munir, A Woetmann and TM Frøsig performed the research. N Odum contributed vital new reagents and edited the manuscript. IM Svane contributed vital new reagents and analytical tools. JC Becker interpreted the data and co-wrote the manuscript. MH Andersen developed the concept and designed the experiments, collected the data, analyzed and interpreted the data and wrote the manuscript.

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Correspondence to M H Andersen.

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Larsen, S., Munir, S., Woetmann, A. et al. Functional characterization of Foxp3-specific spontaneous immune responses. Leukemia 27, 2332–2340 (2013). https://doi.org/10.1038/leu.2013.196

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