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.
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.
Yuan
ZhuQing
Z
Department of Microbiology and Immunology, Center for Primate Biomedical Research, University of Illinois College of Medicine, Chicago, IL 60612, USA.
Wang
Richard
R
Lee
Yuyang
Y
Chen
Crystal Y
CY
Yu
XingBing
X
Wu
ZhongDao
Z
Huang
Dan
D
Shen
Ling
L
Chen
Zheng W
ZW
D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D049109:Cell Proliferation; D011756:Diphosphates / Q000276:immunology*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000502:physiology; D015847:Interleukin-4 / Q000096:biosynthesis / Q000235:genetics* / Q000302:isolation & purification / Q000502:physiology; D008213:Lymphocyte Activation / Q000276:immunology; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008969:Molecular Sequence Data; D009163:Mycobacterium bovis / Q000276:immunology*; D009169:Mycobacterium tuberculosis / Q000276:immunology*; D012326:RNA Splicing / Q000276:immunology; D012333:RNA, Messenger / Q000096:biosynthesis; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism* / Q000382:microbiology
C443995:4-hydroxy-3-methylbut-2-enyl pyrophosphate; D011756:Diphosphates; D036341:Intercellular Signaling Peptides and Proteins; D012333:RNA, Messenger; D016692:Receptors, Antigen, T-Cell, gamma-delta; C421402:interleukin-4 variant; D015847:Interleukin-4