Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide.
Regulatory T cells (T(REGs)) control the key aspects of tolerance and play a role in the lack of antitumor immune responses. Cyclophosphamide (CY) is a chemotherapeutic agent with a dose-dependent, bimodal effect on the immune system. Although a previous study demonstrated that CY reduces the number of T(REGs), the mechanism involved in this process has yet to be defined. In this report, it is established that low-dose CY not only decreases cell number but leads to decreased functionality of T(REGs). CY treatment enhances apoptosis and decreases homeostatic proliferation of these cells. Expression of GITR and FoxP3, which are involved in the suppressive activity of T(REGs), is down-regulated after CY administration, though the level of expression varies depending on the time studied. This is the first report demonstrating that CY, in addition to decreasing cell number, inhibits the suppressive capability of T(REGs). The relevance of the loss of suppressor functionality and the changes in gene expression are further discussed.
Lutsiak
M E Christine
ME
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bldg 10, Rm 8B09, Bethesda, MD 20892, USA.
Semnani
Roshanak T
RT
De Pascalis
Roberto
R
Kashmiri
Syed V S
SV
Schlom
Jeffrey
J
Sabzevari
Helen
H
D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D003520:Cyclophosphamide / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D051858:Forkhead Transcription Factors; D015870:Gene Expression / Q000187:drug effects / Q000276:immunology; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D017475:Receptors, Nerve Growth Factor / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics
D000954:Antigens, Surface; D004268:DNA-Binding Proteins; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053450:Glucocorticoid-Induced TNFR-Related Protein; D007166:Immunosuppressive Agents; D015375:Receptors, Interleukin-2; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C106544:Tnfrsf18 protein, mouse; D003520:Cyclophosphamide