TY - JOUR

T1 - Functional characterization of Foxp3-specific spontaneous immune responses

AU - Larsen, S K

AU - Munir, S

AU - Andersen, Anders Woetmann

AU - Frøsig, T M

AU - Ødum, Niels

AU - Svane, I M

AU - Becker, J C

AU - Andersen, M H

PY - 2013/12

Y1 - 2013/12

N2 - 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.

AB - 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.

KW - Case-Control Studies

KW - Cross Reactions

KW - Enzyme-Linked Immunosorbent Assay

KW - Flow Cytometry

KW - Forkhead Transcription Factors

KW - HLA-A2 Antigen

KW - Humans

KW - Lymphoma, T-Cell, Cutaneous

KW - T-Lymphocytes, Cytotoxic

KW - T-Lymphocytes, Regulatory

U2 - 10.1038/leu.2013.196

DO - 10.1038/leu.2013.196

M3 - Journal article

C2 - 23812418

VL - 27

SP - 2332

EP - 2340

JO - Leukemia

JF - Leukemia

SN - 0887-6924

IS - 12

ER -