title: Phosphoantigen/IL2 expansion and differentiation of Vγ2Vδ2 T cells increase resistance to tuberculosis in nonhuman primates.
abstract: Dominant Vγ2Vδ2 T-cell subset exist only in primates, and recognize phosphoantigen from selected pathogens including M. tuberculosis(Mtb). In vivo function of Vγ2Vδ2 T cells in tuberculosis remains unknown. We conducted mechanistic studies to determine whether earlier expansion/differentiation of Vγ2Vδ2 T cells during Mtb infection could increase immune resistance to tuberculosis in macaques. Phosphoantigen/IL-2 administration specifically induced major expansion and pulmonary trafficking/accumulation of phosphoantigen-specific Vγ2Vδ2 T cells, significantly reduced Mtb burdens and attenuated tuberculosis lesions in lung tissues compared to saline/BSA or IL-2 controls. Expanded Vγ2Vδ2 T cells differentiated into multifunctional effector subpopulations capable of producing anti-TB cytokines IFNγ, perforin and granulysin, and co-producing perforin/granulysin in lung tissue. Mechanistically, perforin/granulysin-producing Vγ2Vδ2 T cells limited intracellular Mtb growth, and macaque granulysin had Mtb-bactericidal effect, and inhibited intracellular Mtb in presence of perforin. Furthermore, phosphoantigen/IL2-expanded Vγ2Vδ2 T effector cells produced IL-12, and their expansion/differentiation led to enhanced pulmonary responses of peptide-specific CD4+/CD8+ Th1-like cells. These results provide first in vivo evidence implicating that early expansion/differentiation of Vγ2Vδ2 T effector cells during Mtb infection increases resistance to tuberculosis. Thus, data support a rationale for conducting further studies of the γδ T-cell-targeted treatment of established TB, which might ultimately help explore single or adjunctive phosphoantigen expansion of Vγ2Vδ2 T-cell subset as intervention of MDR-tuberculosis or HIV-related tuberculosis.
authors: Department of Microbiology and Immunology, Center for Primate Biomedical Research, University of Illinois College of Medicine, Chicago, Illinois, USA.
authors: Crystal Y
authors: CY
authors: Chen
authors: Shuyu
authors: S
authors: Yao
authors: Dan
authors: D
authors: Huang
authors: Huiyong
authors: H
authors: Wei
authors: Helene
authors: H
authors: Sicard
authors: Gucheng
authors: G
authors: Zeng
authors: Hassan
authors: H
authors: Jomaa
authors: Michelle H
authors: MH
authors: Larsen
authors: William R
authors: WR
authors: Jacobs
authors: Richard
authors: R
authors: Wang
authors: Norman
authors: N
authors: Letvin
authors: Yun
authors: Y
authors: Shen
authors: Liyou
authors: L
authors: Qiu
authors: Ling
authors: L
authors: Shen
authors: Zheng W
authors: ZW
authors: Chen
mesh_terms: D000818:Animals; D018893:Bronchoalveolar Lavage; D002454:Cell Differentiation / Q000187:drug effects; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000494:pharmacology; D008168:Lung / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D008252:Macaca fascicularis / Q000378:metabolism / Q000382:microbiology*; D009169:Mycobacterium tuberculosis / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000378:metabolism*; D013601:T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000382:microbiology; D014376:Tuberculosis / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control*
chemical_list: D007376:Interleukin-2; D010750:Phosphoproteins; D016692:Receptors, Antigen, T-Cell, gamma-delta
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