Tuberculosis-Induced Variant IL-4 mRNA Encodes a Cytokine Functioning As Growth Factor for (E)-4-Hydroxy-3-Methyl-But-2-Enyl Pyrophosphate-Specific Vγ2Vδ2 T Cells1

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 V γ 2V δ 2 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 V γ 2V δ 2 T cells, since simultaneously produced IL-4 had only a subtle effect on these γδ T cells. Moreover, VIL-4 seemed to use IL-4R α for signaling and activation, as the VIL-4-induced expansion of V γ 2V δ 2 T cells was blocked by anti-IL-4R α mAb but not anti-IL-4 mAb. Surprisingly, VIL-4-expanded V γ 2V δ 2 T cells after HMBPP stimulation appeared to be heterologous effector cells capable of producing IL-4, IFN- γ , and TNF- α . Thus, mycobacterial infections of macaques induced variant mRNA encoding VIL-4 that functions as growth factor promoting expansion of HMBPP-specific V γ 2V δ 2 T effector cells. The Journal of Immunology , 2009, 182: 811–819.