Differentiation, Distribution and γδ T Cell-Driven Regulation of IL-22-Producing T Cells in Tuberculosis

Abstract

Differentiation, distribution and immune regulation of human IL-22-producing T cells in infections remain unknown. Here, we demonstrated in a nonhuman primate model that M. tuberculosis infection resulted in apparent increases in numbers of T cells capable of producing IL-22 de novo without in vitro Ag stimulation, and drove distribution of these cells more dramatically in lungs than in blood and lymphoid tissues. Consistently, IL-22-producing T cells were visualized in situ in lung tuberculosis (TB) granulomas by confocal microscopy and immunohistochemistry, indicating that mature IL-22-producing T cells were present in TB granuloma. Surprisingly, phosphoantigen HMBPP activation of Vγ2Vδ2 T cells down-regulated the capability of T cells to produce IL-22 de novo in lymphocytes from blood, lung/BAL fluid, spleen and lymph node. Up-regulation of IFNγ-producing Vγ2Vδ2 T effector cells after HMBPP stimulation coincided with the down-regulated capacity of these T cells to produce IL-22 de novo. Importantly, anti-IFNγ neutralizing Ab treatment reversed the HMBPP-mediated down-regulation effect on IL-22-producing T cells, suggesting that Vγ2Vδ2 T-cell-driven IFNγ-networking function was the mechanism underlying the HMBPP-mediated down-regulation of the capability of T cells to produce IL-22. These novel findings raise the possibility to ultimately investigate the function of IL-22 producing T cells and to target Vγ2Vδ2 T cells for balancing potentially hyper-activating IL-22-producing T cells in severe TB.

Characterization of CD4/CD8+ αβ and Vγ2Vδ2+ T cells in HIV-negative individuals with different Mycobacterium tuberculosis infection statuses

“…Blood samples collected freshly from all groups of participants were handled, and analyzed by phenotyping and intracellular cytokine staining (ICS) at the biocontainment laboratory [12]. Peripheral blood mononuclear cells (PBMCs) were isolated from heparin-anticoagulated blood by density gradient sedimentation using Lympholyte-H (Cedarlane Laboratories Ltd, Ontario, Canada).…”

“…HMBPP belongs to phosphoantigen and only TCRs bearing both the Vγ2 and Vδ2 elements can recognize HMBPP. The phosphoantigen compound HMBPP used in the study was 98% pure and specifically stimulated the activation/expansion of Vγ2Vδ2 T cells but not other cell subpopulations [12].…”

“…Thus, CD4+ T cells may migrate from the 10 peripheral blood to the lesion site. 11 To investigate antigen-specific T cell immune responses at the lesion site, we detected 12 PPD-specific IFN-γ-secreting CD4+ and CD8+ T cells and HMBPP-specific 13 IFN-γ-secreting Vγ2Vδ2+ T cells in the PFMCs of patients with tuberculous pleurisy. 14 The ICS results indicated that antigen-specific CD4+ T cells predominated among 15 CD3+ T cells in the PFMCs, while antigen-specific CD8+ and Vγ2Vδ2+ T cells only 16 accounted for a small proportion ( Figure 3C, 3D).…”

“…CD4+ T cells play an important role primarily through the secretion of interferon-gamma (IFN-γ), interleukin -2 (IL-2), tumor necrosis factor-α (TNF-α) and other cytokines that are involved in immune control [4][5][6]. CD8+ T cells and γδ T cells play protective roles through the secretion of IFN-γ, perforin and granzyme [5][6][7][8][9][10][11][12][13]. Our previous studies in HIV/AIDS patients showed that cytokine secretion by M.tb antigen-specific CD8+ and Vγ2Vδ2+ T cells was greatly enhanced in subjects with latent tuberculosis infection compared with subjects with active tuberculosis.…”

Interleukin-22 Promotes T Helper 1 (Th1)/Th17 Immunity in Chlamydial Lung Infection

“…For bacterial infection, it is generally accepted that IL-22 plays a protective role in extracellular bacterial infections, such as Citrobactor rodentium (6), Klebsiella pneumoniae (7) and segmented filamentous bacterium (SFB) (12), but its role in intracellular bacterial infections remains largely unclear. In the limited studies on intracellular bacterial infections, IL-22 was found redundant for Francisella tularensis (13) and Listeria monocytogenes (14) infections, although its role in Mycobacterium tuberculosis infection appeared inconsistent (15,16).…”