AUTHOR=Yang Rui , Yao Lan , Shen Ling , Sha Wei , Modlin Robert L. , Shen Hongbo , Chen Zheng W. 

TITLE=IL-12 Expands and Differentiates Human Vγ2Vδ2 T Effector Cells Producing Antimicrobial Cytokines and Inhibiting Intracellular Mycobacterial Growth

JOURNAL=Frontiers in Immunology

VOLUME=Volume 10 - 2019

YEAR=2019

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.00913

DOI=10.3389/fimmu.2019.00913

ISSN=1664-3224

ABSTRACT=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 in addition to CD4+ T cells. Published studies suggest that predominant Vγ2Vδ2 T cells in humans/nonhuman primates 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 M. tuberculosis or others. However, such fast-acting and Th1 features of Vγ2Vδ2 T cells have not been linked to IL-12 immune regulation. Here, we showed that IL-12, not other IL-12 family members IL-27/IL-33, apparently expanded HMBPP-activated Vγ2Vδ2 T cells. Although IL-12 and IL-2 similarly expanded HMBPP-activated Vγ2Vδ2 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 Vγ2Vδ2 T cells required the PI3K/AKT and STAT4 activation pathways and endogenous TNF-α signaling, but did not involve p38/MAPK or IFN-γ signals. IL-12-expanded Vγ2Vδ2 T cells exhibited CD28+ central/effector memory phenotypes and differentiated into polyfunctional effector cell subtypes which expressed TBX21/T-bet, antimicrobial cytokines IFN-γ, TNF-α, GM-CSF and cytotoxic granule molecules. Furthermore, the IL-12-expanded Vγ2Vδ2 T cells inhibited the growth of intracellular mycobacteria in IFN-γ- or TNF-α-dependent fashion. Our findings support the concept that IL-12 drives early development of fast-acting Vγ2Vδ2 T effector cells in antimicrobial immune responses.