Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide

M E Christine Lutsiak; Roshanak T Semnani; Roberto De Pascalis; Syed V S Kashmiri; Jeffrey Schlom; Helen Sabzevari

doi:10.1182/blood-2004-06-2410

Inhibition of CD4(+)25+ T regulatory cell function implicated in enhanced immune response by low-dose cyclophosphamide

Blood. 2005 Apr 1;105(7):2862-8. doi: 10.1182/blood-2004-06-2410. Epub 2004 Dec 9.

Authors

M E Christine Lutsiak¹, Roshanak T Semnani, Roberto De Pascalis, Syed V S Kashmiri, Jeffrey Schlom, Helen Sabzevari

Affiliation

¹ 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.

PMID: 15591121
DOI: 10.1182/blood-2004-06-2410

Abstract

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.

Publication types

Research Support, U.S. Gov't, P.H.S.

MeSH terms

Animals
Antigens, Surface / genetics
Antigens, Surface / immunology
Apoptosis / drug effects
Apoptosis / immunology
B-Lymphocytes / cytology
B-Lymphocytes / drug effects
B-Lymphocytes / immunology
CD4-Positive T-Lymphocytes / cytology
CD4-Positive T-Lymphocytes / drug effects*
CD4-Positive T-Lymphocytes / immunology*
Cell Differentiation / drug effects
Cell Differentiation / immunology
Cyclophosphamide / pharmacology*
DNA-Binding Proteins / genetics
Female
Forkhead Transcription Factors
Gene Expression / drug effects
Gene Expression / immunology
Glucocorticoid-Induced TNFR-Related Protein
Immunosuppressive Agents / pharmacology*
Mice
Mice, Inbred C57BL
Receptors, Interleukin-2 / metabolism
Receptors, Nerve Growth Factor / genetics
Receptors, Tumor Necrosis Factor / genetics

Substances

Antigens, Surface
DNA-Binding Proteins
Forkhead Transcription Factors
Foxp3 protein, mouse
Glucocorticoid-Induced TNFR-Related Protein
Immunosuppressive Agents
Receptors, Interleukin-2
Receptors, Nerve Growth Factor
Receptors, Tumor Necrosis Factor
Tnfrsf18 protein, mouse
Cyclophosphamide