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7081721 
Journal Article 
IL-12 Expands and Differentiates Human V gamma 2V delta 2 T Effector Cells Producing Antimicrobial Cytokines and Inhibiting Intracellular Mycobacterial Growth 
Yang, Rui; Yao, Lan; Shen, L; Sha, Wei; Modlin, RL; Shen, H; Chen, ZW; , 
2019 
1 
Frontiers in Immunology
EISSN: 1664-3224 
FRONTIERS MEDIA SA 
LAUSANNE 
31080452 
WOS:000465743500002 
While IL-12 plays a key role in differentiation of protective CD4(+) Th1 response, little is known about mechanisms whereby IL-12 differentiates other T-cell populations. Published studies suggest that predominant V gamma 2V delta 2 T cells in humans/nonhuman primates (NHP) are a fast-acting T-cell subset, with capacities to rapidly expand and produce Th1 and cytotoxic cytokines in response to phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) produced by Mycobacterium tuberculosis (Mtb) or others. However, whether IL-12 signaling pathway mediates fast-acting and Th1 or anti-microbial features of V gamma 2V delta 2 T cells remains poorly defined. Here, we show that IL-12, but not other IL-12 family members IL-27/IL-35, apparently expanded HMBPP-activated V gamma 2V delta 2 T cells. Although IL-12 and IL-2 similarly expanded HMBPP-activated V gamma 2V delta 2 T-cell clones, the IL-12-induced expansion did not require endogenous IL-2 or IL-2 co-signaling during HMBPP + IL-12 co-treatment. IL-12-induced expansion of V gamma 2V delta 2 T cells required the PI3K/AKT and STAT4 activation pathways and endogenous TNF-alpha signaling but did not involve p38/MAPK or IFN-gamma signals. IL-12-expanded V gamma 2V delta 2 T cells exhibited central/effector memory phenotypes and differentiated into polyfunctional effector cell subtypes which expressed TBX21/T-bet, antimicrobial cytokines IFN-gamma, TNF-alpha, GM-CSF, and cytotoxic granule molecules. Furthermore, the IL-12-expanded V gamma 2V delta 2 T cells inhibited the growth of intracellular mycobacteria in IFN-gamma- or TNF-alpha-dependent fashion. Our findings support the concept that IL-12 drives early development of fast-acting V gamma 2V delta 2 T effector cells in antimicrobial immune responses.