Abstract
Foxp3 is a central control element in the development and function of regulatory T cells (Treg), and mice expressing a diphtheria toxin (DT) receptor-enhanced green fluorescent protein fusion protein under the control of the foxp3 gene locus (DEREG mice) allow conditional and efficient depletion of Foxp3(+) Treg by DT injection. Herein, we use DEREG mice and a mouse model of carcinogenesis to show that conditional and effective Treg depletion can both protect mice from carcinogenesis by innate control, yet permanently eradicate a proportion of de novo-established tumors in mice in a largely CD8(+) T-cell- and IFN-γ-dependent manner. Tumors displayed a heterogeneous response to Treg depletion, and suppression of established tumors was accompanied by an increase in the tumor-infiltrating CD8(+) T-cell/B-cell ratio. Tumor rejection occurred in the absence of overt autoimmunity, suggesting that effective transient Treg depletion strategies may be therapeutic in at least a proportion of spontaneous tumors developing in the host.
Highlights
Occurring CD25+CD4+ regulatory T cells (Treg) have a major importance in modulating host responses to tumors and infections, in preventing transplant rejection, and in inhibiting the development of autoimmunity and allergy [1,2,3]
depletion of regulatory T cell” (DEREG) mice have an enhanced green fluorescent protein (eGFP) expression pattern similar to that of previously published Foxp3 reporter mice [13, 14], and diphtheria toxin (DT) treatment, in contrast to conventional Treg depletion strategies, allows for efficient and selective depletion of Foxp3+ cells without affecting CD25+ effector T cells [12]. It has been previously shown, using anti-CD25 and antiFR4 antibodies, that Treg depletion before, or at the time of, tumor inoculation can lead to an efficient antitumor effector response that suppresses and, in some cases, prevents tumor formation and growth [6, 9, 15,16,17]
C57BL/6 DEREG mice carry a diphtheria toxin receptor (DTR)-eGFP transgene under the control of an additional Foxp3 promoter, whereby DT application leads to Treg depletion at any desired time point during an ongoing immune response [12]
Summary
Occurring CD25+CD4+ regulatory T cells (Treg) have a major importance in modulating host responses to tumors and infections, in preventing transplant rejection, and in inhibiting the development of autoimmunity and allergy [1,2,3]. CD4+ Treg were identified exclusively by the constitutive expression of CD25, and many in vivo experiments have been performed using depleting antibodies directed against CD25 [4, 5] or folate receptor 4 Bacterial artificial chromosome–transgenic mice, termed “depletion of regulatory T cell” (DEREG) mice, express a diphtheria toxin receptor (DTR)–enhanced green fluorescent protein (eGFP) fusion protein under the control of the foxp locus, allowing both the detection and inducible depletion of Foxp3+ Treg [12]. DEREG mice have an eGFP expression pattern similar to that of previously published Foxp reporter mice [13, 14], and DT treatment, in contrast to conventional Treg depletion strategies, allows for efficient and selective depletion of Foxp3+ cells without affecting CD25+ effector T cells [12]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
