A functional toll-interacting protein variant is associated with Bacillus calmette-guérin–specific immune responses and tuberculosis
American journal of respiratory and critical care medicine, 2017•atsjournals.org
Rationale: The molecular mechanisms that regulate tuberculosis susceptibility and bacillus
Calmette-Guérin (BCG)-induced immunity are mostly unknown. However, induction of the
adaptive immune response is a critical step in host control of Mycobacterium tuberculosis.
Toll-interacting protein (TOLLIP) is a ubiquitin-binding protein that regulates innate immune
responses, including Toll-like receptor signaling, which initiate adaptive immunity. TOLLIP
variation is associated with susceptibility to tuberculosis, but the mechanism by which it …
Calmette-Guérin (BCG)-induced immunity are mostly unknown. However, induction of the
adaptive immune response is a critical step in host control of Mycobacterium tuberculosis.
Toll-interacting protein (TOLLIP) is a ubiquitin-binding protein that regulates innate immune
responses, including Toll-like receptor signaling, which initiate adaptive immunity. TOLLIP
variation is associated with susceptibility to tuberculosis, but the mechanism by which it …
Rationale: The molecular mechanisms that regulate tuberculosis susceptibility and bacillus Calmette-Guérin (BCG)-induced immunity are mostly unknown. However, induction of the adaptive immune response is a critical step in host control of Mycobacterium tuberculosis. Toll-interacting protein (TOLLIP) is a ubiquitin-binding protein that regulates innate immune responses, including Toll-like receptor signaling, which initiate adaptive immunity. TOLLIP variation is associated with susceptibility to tuberculosis, but the mechanism by which it regulates tuberculosis immunity is poorly understood.
Objectives: To identify functional TOLLIP variants and evaluate the role of TOLLIP variation on innate and adaptive immune responses to mycobacteria and susceptibility to tuberculosis.
Methods: We used human cellular immunology approaches to characterize the role of a functional TOLLIP variant on monocyte mRNA expression and M. tuberculosis–induced monocyte immune functions. We also examined the association of TOLLIP variation with BCG-induced T-cell responses and susceptibility to latent tuberculosis infection.
Measurements and Main Results: We identified a functional TOLLIP promoter region single-nucleotide polymorphism, rs5743854, which was associated with decreased TOLLIP mRNA expression in infant monocytes. After M. tuberculosis infection, TOLLIP-deficient monocytes demonstrated increased IL-6, increased nitrite, and decreased bacterial replication. The TOLLIP-deficiency G/G genotype was associated with decreased BCG-specific IL-2+ CD4+ T-cell frequency and proliferation. This genotype was also associated with increased susceptibility to latent tuberculosis infection.
Conclusions: TOLLIP deficiency is associated with decreased BCG-specific T-cell responses and increased susceptibility to tuberculosis. We hypothesize that the heightened antibacterial monocyte responses after vaccination of TOLLIP-deficient infants are responsible for decreased BCG-specific T-cell responses. Activating TOLLIP may provide a novel adjuvant strategy for BCG vaccination.
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