Halofuginone suppresses T cell proliferation by blocking proline uptake and inducing cell apoptosis.

Abstract

Inactivation of T cells is a widely used strategy for immunosuppression. Halofuginone (HF) is an antiprotozoal agent for treating parasites in veterinary medicine, and has been demonstrated to inhibit collagen type 1 synthesis, T helper 17 cell differentiation and cytokine production in activated T cells. The present study was designed to examine the biological effects of HF against T cell receptor and interleukin (IL)-2 stimulated T cell proliferation. T cell proliferation in cultured murine splenocytes was determined by methylthiazol tetrazolium assay. Cell apoptosis was mainly determined by fluorescence-activated cell sorting with Annexin-V and 7-aminoactinomycin D staining. Here, we showed that HF significantly suppressed T cell proliferation in naïve splenocyte cultures in response to alloantigen or anti-CD3 antibody (IC₅₀, 2-2.5 nM; P<0.0001), or in activated T cell cultures in response to IL-2 (IC₅₀, 16 nM; P<0.0001) in a dose-dependent manner. HF did neither attenuate IL-2 production in anti-CD3 antibody activated T cells nor disrupt STAT5 signaling in IL-2-stimulated T cells, but its anti-T cell proliferation was correlated with an increase in cell apoptosis and a decrease in proline uptake in culture medium. Further experiments showed that proline supplement in cell culture medium significantly prevented HF-mediated suppression of T cell proliferation and cell apoptosis. In conclusion, these data suggest that HF interferes with proline incorporation or uptake, resulting in apoptosis via amino acid starvation response in T cells in the response to antigen/mitogen or IL-2 stimulation.

• Authors: Tony L H Chu, Qiunong Guan, Christopher Y C Nguan, Caigan Du
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 16 Issue 4 Pg. 414-23 (Aug 2013) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 23685128 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier B.V. All rights reserved.

Chemical References

• Antiprotozoal Agents
• Culture Media
• Interleukin-2
• Piperidines
• Quinazolinones
• Receptors, Antigen, T-Cell
• Proline
• halofuginone

Topics

• Animals
• Antiprotozoal Agents (pharmacology)
• Apoptosis (drug effects)
• Cell Culture Techniques
• Cell Proliferation (drug effects)
• Cells, Cultured
• Culture Media
• Dose-Response Relationship, Drug
• Flow Cytometry
• In Situ Nick-End Labeling
• Interleukin-2 (immunology, metabolism)
• Lymphocyte Activation (drug effects)
• Mice
• Mice, Inbred BALB C
• Piperidines (pharmacology)
• Proline (metabolism)
• Quinazolinones (pharmacology)
• Receptors, Antigen, T-Cell (immunology, metabolism)
• Spleen (cytology, immunology)
• T-Lymphocytes (drug effects, immunology, metabolism, pathology)