Abstract
The role of B cells migrating to the lung and forming follicles during tuberculosis (TB) inflammation is still the subject of debate. In addition to their antibody production and antigen-presenting functions, B cells secrete different cytokines and chemokines, thus participating in complex networks of innate and adaptive immunity. Importantly, lung B-cells produce high amounts of the pleiotropic gp130 cytokine IL-6. Its role during TB infection remains controversial, partly due to the fact that IL-6 is produced by different cell types. To investigate the impact of IL-6 produced by B cells on TB susceptibility and immune responses, we established a mouse strain with specific IL-6 deficiency in B cells (CD19cre-IL-6fl/fl, B-IL-6KO) on the B6 genetic background. Selective abrogation of IL-6 in B cells resulted in shortening the lifespan of TB-infected B-IL-6KO mice compare to the wild-type controls. We provide evidence that at the initial TB stages B cells serve as a critical source of IL-6. In the lung, the effect of IL-6 deficiency in B cells is associated rather with B and T cell functioning, than with macrophage polarization. TB-infected B-IL-6KO mice displayed diminished sizes of B cells themselves, CD4+IFN-γ+, Th17+, and CD4+CXCR5+ follicular T cell populations. The pleiotropic effect of B-cell-derived IL-6 on T-cells demonstrated in our study bridges two major lymphocyte populations and sheds some light on B- and T-cells interactions during the stage of anti-TB response when the host switches on a plethora of acquired immune reactions.
Highlights
Tuberculosis (TB) remains a global health problem, affecting about 10 million people and claiming about 1.2 – 1.5 million lives annually [1]
It was shown that in mice with genetically disrupted il6 gene in all cells i. v. challenge with virulent M. tuberculosis resulted in a more rapid mortality compared to the wild type mice [15]
IL-6 production by many different cells may potentially have different effects on inflammation, which requires the application of mouse strains with cell type-specific KO mutations for il6 or its receptor genes for experimental dissection of the effects of IL-6 from diverse cell sources on different cells
Summary
Tuberculosis (TB) remains a global health problem, affecting about 10 million people and claiming about 1.2 – 1.5 million lives annually [1]. B-Cell Derived IL-6 in Tuberculosis apparently play many different roles in anti-TB response by producing cytokines/chemokines, serving as antigen-presenting cells, and interacting with other immune cells during lung inflammation [reviewed [4, 6, 7]]. Regarding B-cell cytokine production, it was shown in animal models that B cells from TBaffected lung secrete almost no IL-2, high amounts of IL-6, IL-11, and IL-17, and low amounts of IL-10, IFN-g, and TNF-a [8, 9]. Produced in low amounts, TNF-a from B cells is involved in the formation of lung BCFs in TB-infected mice [10]. Both in mice and TB patients, it was demonstrated that B cells display a STAT1-centered gene expression signature, produce type 1 interferons [11] and secrete IL-35 [12, 13]. Specific activities of IL-6 produced by B-cells remain obscure despite its abundance in TB-infected lungs [8, 9]
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