Abstract
Following infection with Mycobacterium tuberculosis (M.tb), children are more susceptible to develop disease particularly extrapulmonary disease than adults. The exact mechanisms required for containment of M.tb are not known, but would be important to identify correlates of protection. To comprehensively analyze key immune responses to mycobacteria between HIV-negative children with extrapulmonary TB (EPTB) compared to children with pulmonary TB (PTB) or healthy controls. Whole blood was stimulated in vitro with mycobacteria for 24 h or 6 days to induce effector and memory responses. CD4, CD8, γδ, regulatory T cells, and their related cytokines were measured. Samples of children with tuberculosis (TB) disease were analyzed both at time of diagnosis and at the end of TB treatment to determine if any differences were due to TB disease or an underlying host phenotype. Seventy-six children with TB disease (48 with PTB and 28 with EPTB) and 83 healthy controls were recruited to the study. The frequency of CD4+CD25+CD39+FOXP3+ regulatory T cells and secreted IL10 were significantly higher in children with TB compared to healthy controls. IFNγ-, IL17-, and IL22-producing γδ T cells, IL22-producing CD4+ T cells and secreted pro-inflammatory cytokines (IFNγ, IL1β, and TNFα) were significantly lower in children with TB disease compared to healthy controls. IFNγ-producing CD4+ T cells and Ki67+-proliferating CD4+ T cells, however, were present in equal numbers in both groups. Following treatment, these immune parameters recovered to "healthy" levels or greater in children with PTB, but not those with extrapulmonary TB. In children with TB disease, a predominantly immune regulatory state is present. These immune findings do not distinguish between children with PTB and EPTB at the time of diagnosis. Following treatment, these inflammatory responses recover in PTB, suggesting that the effect is disease specific rather than due to an underlying host defect.
Highlights
Of the estimated 10.4 million new cases of tuberculosis (TB) annually, at least 1million (10%) occurred in children [1]
Children have a higher risk of progression to disease and of dissemination or extrapulmonary TB (EPTB) and death, and this risk decreases with increasing age [2, 3]
Children between birth and 16 years were enrolled to three different groups: pulmonary TB (PTB) disease, extrapulmonary TB (EPTB) disease, and healthy, non-M.tb sensitized children
Summary
Of the estimated 10.4 million new cases of tuberculosis (TB) annually, at least 1million (10%) occurred in children [1]. Recent studies report a lack of correlation between immune protection imparted by BCG and IFNγ, produced by CD4+ T cells [4, 5] These data support the notion that CD4+ T cells and IFNγ are important components of an effective antimycobacterial immune response, they do not fully explain observed differences in host susceptibility to TB. Other cell types, such as γδ, Th17, and regulatory T cells are considered important, but these T cell populations have not been studied in children with PTB or EPTB [6, 7]. The exact mechanisms required for containment of M.tb are not known, but would be important to identify correlates of protection
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