Tuberculosis-induced variant IL-4 mRNA encodes a cytokine functioning as growth factor for (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate-specific Vgamma2Vdelta2 T cells

• Published in: The Journal of immunology (1950) Vol. 182; no. 2; pp. 811 - 819
• Main Authors: Yuan, ZhuQing, Wang, Richard, Lee, Yuyang, Chen, Crystal Y, Yu, XingBing, Wu, ZhongDao, Huang, Dan, Shen, Ling, Chen, Zheng W
• Format: Journal Article
• Language: English
• Published: United States 15.01.2009
• Subjects: Amino Acid Sequence; Animals; Base Sequence; Cell Proliferation; Diphosphates - immunology; Intercellular Signaling Peptides and Proteins - biosynthesis; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - physiology; Interleukin-4 - biosynthesis; Interleukin-4 - genetics; Interleukin-4 - isolation & purification; Interleukin-4 - physiology; Lymphocyte Activation - immunology; Macaca fascicularis; Macaca mulatta; Molecular Sequence Data; Mycobacterium bovis - immunology; Mycobacterium tuberculosis - immunology; Receptors, Antigen, T-Cell, gamma-delta - immunology; RNA Splicing - immunology; RNA, Messenger - biosynthesis; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; T-Lymphocyte Subsets - microbiology
• ISSN: 1550-6606

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 Vgamma2Vdelta2 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 Vgamma2Vdelta2 T cells, since simultaneously produced IL-4 had only a subtle effect on these gammadelta T cells. Moreover, VIL-4 seemed to use IL-4R alpha for signaling and activation, as the VIL-4-induced expansion of Vgamma2Vdelta2 T cells was blocked by anti-IL-4R alpha mAb but not anti-IL-4 mAb. Surprisingly, VIL-4-expanded Vgamma2Vdelta2 T cells after HMBPP stimulation appeared to be heterologous effector cells capable of producing IL-4, IFN-gamma, and TNF-alpha. Thus, mycobacterial infections of macaques induced variant mRNA encoding VIL-4 that functions as growth factor promoting expansion of HMBPP-specific Vgamma2Vdelta2 T effector cells.