Abstract
Interleukin-2 (IL-2) inducible T-cell kinase (ITK) is a non-receptor tyrosine kinase highly expressed in T-cell lineages and regulates multiple aspects of T-cell development and function, mainly through its function downstream of the T-cell receptor. Itk deficiency can lead to CD4 lymphopenia and Epstein-Bar virus (EBV)-associated lymphoproliferation and recurrent pulmonary infections in humans. However, the role of the ITK signaling pathway in pulmonary responses in active tuberculosis due to Mtb infection is not known. We show here that human lungs with active tuberculosis exhibit altered T-cell receptor/ITK signaling and that Itk deficiency impaired early protection against Mtb in mice, accompanied by defective development of IL-17A-producing γδ T cells in the lungs. These findings have important implications of human genetics associated with susceptibility to Mtb due to altered immune responses and molecular signals modulating host immunity that controls Mtb activity. Enhancing ITK signaling pathways may be an alternative strategy to target Mtb infection, especially in cases with highly virulent strains in which IL-17A plays an essential protective role.
Highlights
Mycobacterium tuberculosis (Mtb) is the causative agent of what remains one of the most insidious and invasive human infections, responsible for millions of cases of active lung diseases and deaths per year in the world [WHO Global Tuberculosis Report, [1] and O’Garra et al [2]]
Given the observation that the T-cell receptor (TCR) signaling pathway was upregulated in the face of active TB in human lungs and that inducible T-cell kinase (ITK) is a critical score-driving gene for the pathway enrichment (Figure 1), we sought to determine the role of ITK in host responses to Mtb infection
In murine models of Itk deficiency, despite no difference in animal mortality, we found that Mtb bacterial burden was significantly higher in the lungs in the absence of ITK 4 weeks post-Mtb infection (Figure 2A)
Summary
Mycobacterium tuberculosis (Mtb) is the causative agent of what remains one of the most insidious and invasive human infections, responsible for millions of cases of active lung diseases and deaths per year in the world [WHO Global Tuberculosis Report, [1] and O’Garra et al [2]]. Genetic and environmental factors of the host associated with primary and acquired immunodeficiency can lead to an increased risk of developing active tuberculosis that presents severe pulmonary illness in the clinic [2, 4]. ITK deficiency in humans is associated with primary immunodeficiency, progressive natural killer T (NKT) and CD4+ T-cell lymphopenia, elevated susceptibility to EpsteinBar virus (EBV), and EBV-driven lymphoproliferative diseases, in which frequent pulmonary involvement has emerged as a clinical hallmark [6,7,8,9,10,11,12,13]. Human T cells from patients with ITK deficiency exhibit impaired responses to TCR activation, with reduced generation of Th17 cells and production of the associated cytokines IL-17A, IL22, and granulocyte-macrophage colony-stimulating factor [14]. Analysis of Itk−/− mice reveals altered γδ T-cell development [46,47,48,49]; the presence and function of γδ T cells has not been evaluated in ITKdeficient humans
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