Regulation of the TH22 Response by TGF-β, during Multidrug-Resistant Tuberculosis

B R IMPERIALE; GAMBERALE A; CORREA M; GARCIA A; BARTOLETTI B; AIDAR O; GONZALEZ MONTANER P; PALMERO DJ; DE LA BARREA SILVIA

Breckenridge, Denver

Simposio; Keystone Symopsia: A Research Reboot of Tuberculosis; 2022

Tuberculosis (TB) remains a major global health problem and is the second leading cause of death from infectious diseases worldwide. During active pulmonary TB, TH1 cytokines (CK) are mainly produced in the earliest stages of the disease, and in addition to this response, other lymphocytes such as TH22 would participate in that response. Interleukin-22 (IL-22) is produced by several immune cells including T cells. IL-22 has been attributed a dual role during TB, it can act on the mucous membrane promoting tissue repair or inducing inflammatory processes, depending on the CK microenvironment. On the other hand, TGF-β efficiently suppresses cellular immunity and inhibits lymphocytes proliferation, especially mature T lymphocytes. Then, the aim of this study was to explore the role of the TGF-β in the in vitro TH22 response during multidrug-resistant TB (MDR-TB). Peripheral blood samples were obtained from patients with MDR-TB, and healthy donors (HDs). TGF-β and IL-22 plasma levels were measured by ELISA. Peripheral blood mononuclear cells (PBMCs) were isolated and cultured with γ-irradiated MDR Mycobacterium tuberculosis (Mtb) strains in the presence or absence of neutralizing anti TGF-β monoclonal antibody. IL-22 secretion from PBMC cultures supernatants was measured by ELISA while CD4+ and CD8+ intracellular IL-22 expression was determined by flow cytometry.TGF-β levels in plasma were higher in MDR-TB patients than in HDs. TGF-β plasma levels in MDR-TB patients inversely correlated with IL-22 plasma levels. TGF-β neutralization increased IL-22 secretion in PBMC culture supernatants and intracellular IL-22 expression in CD4+ and CD8+ T cells. Besides, the higher the plasma levels of TGF-β, the lower the levels of IL-22 expression on CD4+ and CD8+ T cells, and the greater the severity of lung injury.These results would suggest that TGF-β would negatively modulate systemic and in vitro Mtb-induced secretion and expression of IL-22 by CD4+ and CD8+ T cells in MDR-TB patients affecting in turn host ability to control Mtb growth and lung tissue repair.