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Tuberculosis-Induced Variant IL-4 mRNA Encodes a Cytokine Functioning As Growth Factor for (E)-4-Hydroxy-3-Methyl-But-2-Enyl Pyrophosphate-Specific V2V2 T Cells¹

ZhuQing Yuan^*,, Richard Wang^*, Yuyang Lee^*, Crystal Y. Chen^*, XingBing Yu, ZhongDao Wu, Dan Huang^*, Ling Shen and Zheng W. Chen^2,*

^* Department of Microbiology and Immunology, Center for Primate Biomedical Research, University of Illinois College of Medicine, Chicago, IL 60612; Department of Parasitology, The School of Pre-clinical Medicine, Sun Yat-sen University, Guangzhou, China; and Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA 02212

The possibility that mycobacterial infections induce variant cytokine mRNA encoding a functionally distinct protein for immune regulation has not been addressed. In this study, we reported that Mycobacterium tuberculosis and bacillus Calmette-Guérin infections of macaques induced expression of variant IL-4 (VIL-4) mRNA encoding a protein comprised of N-terminal 97 aa identical with IL-4, and unique C-terminal 96 aa including a signaling-related proline-rich motif. While VIL-4 could be stably produced as intact protein, the purified VIL-4 induced apparent expansion of phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP)-specific V2V2 T cells in dose- and time-dependent manners. The unique C-terminal 96 aa bearing the proline-rich motif (PPPCPP) of VIL-4 appeared to confer the ability to expand V2V2 T cells, since simultaneously produced IL-4 had only a subtle effect on these T cells. Moreover, VIL-4 seemed to use IL-4R for signaling and activation, as the VIL-4-induced expansion of V2V2 T cells was blocked by anti-IL-4R mAb but not anti-IL-4 mAb. Surprisingly, VIL-4-expanded V2V2 T cells after HMBPP stimulation appeared to be heterologous effector cells capable of producing IL-4, IFN-, and TNF-. Thus, mycobacterial infections of macaques induced variant mRNA encoding VIL-4 that functions as growth factor promoting expansion of HMBPP-specific V2V2 T effector cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by the National Institutes of Health R01 Grants HL64560 and RR13601 (both to Z.W.C.).

² Address correspondence and reprint requests to Prof. Zheng W. Chen, 835 South Wolcott Avenue, Mail Code 790, Chicago, IL 60612. E-mail address: zchen{at}uic.edu

³ Abbreviations used in this paper: VIL-4, variant IL-4; HMBPP, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate; BCG, bacillus Calmette-Guérin.

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The JI 2009 182: 739-740. [Full Text]