Tuberculous pleurisy drives marked effector responses of γδ, CD4+, and CD8+ T cell subpopulations in humans

Abstract

Although tuberculous pleurisy (TP) presumably involves a hypersensitivity reaction, there is limited evidence indicating overreactive effector responses of γδ T cells and αβ T cells and their interrelation with Foxp3(+) Tregs in pleural and other compartments. We found that TP induced reciprocal representations of Foxp3(+) Tregs and Mtb phosphoantigen-specific Vγ2Vδ2 T cells in different anatomic compartments. Patients with TP exhibited appreciable numbers of "proliferating" Ki-67(+) Vγ2Vδ2 T cells in the airway where Foxp3(+) Tregs were not dominant, whereas striking increases in Foxp3(+) Tregs in the blood and pleural compartments coincided with low frequencies of Vγ2Vδ2 T cells. Interestingly, anti-tuberculosis chemotherapy control of Mtb infection in patients with TP reversed reciprocal representations of Foxp3(+) Tregs and proliferating Vγ2Vδ2 T cells. Surprisingly, despite high-level Foxp3(+) Tregs, TP appeared to drive overreactive responses of IFN-γ-producing Vγ2Vδ2, CD4(+)CD25(+), and CD8(+)CD25(+) T effector subpopulations, whereas IL-22-producing Vγ2Vδ2 T cells increased subtly. Th1 effector responses were sustained despite remarkable declines in Foxp3(+) Tregs at 1 mo after the treatment. Overreactive T effector responses of Mtb-reactive γδ T cells, αβ CD25(+)CD4(+), and CD25(+)CD8(+) T cell subpopulations appear to be immune features for TP. Increased Foxp3(+) Tregs might be responsive to overreactive TP but unable to influence T effector responses despite having an inverse relation with proliferating Vγ2Vδ2 T cells.

Tuberculosis-sensitized monocytes sustain immune response of interleukin-37

“…1D). We then used an intracellular cytokines staining method (Zeng et al, 2015) to detect IL-37 in PBMCs using an IL-37b monoclonal antibody. Surprisingly, we found that IL-37b was predominantly produced in monocytes, but not lymphocytes in ATB patients and HCs, and the frequency of IL-37b-producing monocytes in ATB patients was higher than that in HCs (Fig.…”

“…Of note, we recently demonstrated the specificity and utility for direct ICS assay detecting intracellular cytokines without a need for antigen stimulation (Zeng et al, 2015). We therefore employed this useful direct ICS approach and demonstrated that monocytes not lymphocytes served as one of sources of IL-37b-production in ATB patients.…”

“…A total of 48 cases of active pulmonary tuberculosis (ATB) diagnosed as previously described (Zeng et al, 2015) were recruited from Dongguang 6st People’s Hospital (Dongguan, China). ATB was confirmed based on typical clinical symptoms, chest X-radiography, positive Ziehl-Neelsen acid fast bacilli staining, positive Lowenstein-Jensen slants bacterial culture for sputum, or apparent anti-TB drugs efficacy.…”

“…Peripheral blood mononuclear cells (PBMCs) were prepared as previously reported (Zeng et al, 2015). Briefly, approximately 5 mL blood was collected from each subject in an acid citrate dextrose (ACD)-containing blood collection tube.…”

“…The expression of IL-37b in monocytes was determined with intracellular flow cytometry staining (Zeng et al, 2015). PBMCs (10 × 10 6 ) were fixed and permeabilized using a Fixation/Permeabilization kit, followed by staining with a mouse anti-human IL-37b antibody for 30 min and goat anti-mouse IgG/IgM-FITC for 20 min.…”