A Functional TOLLIP Variant is Associated with BCG-Specific Immune Responses and Tuberculosis.

Publication Type:

Journal Article

Source:

American journal of respiratory and critical care medicine (2017)

Abstract:

RATIONALE: The molecular mechanisms that regulate tuberculosis susceptibility and BCG-induced immunity are mostly unknown. However, induction of the adaptive immune response is a critical step in host control of M. tuberculosis. TOLLIP is a ubiquitin-binding protein that regulates innate immune responses, including TLR 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 TB infection.

MEASUREMENTS AND MAIN RESULTS: We identified a functional TOLLIP promoter region SNP, 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 following 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.