At least one third of the world's population is infected with Mycobacterium tuberculosis (Mtb). Consequently, tuberculosis (TB) remains one of the most significant causes of childhood morbidity and mortality worldwide (1). Young children bear the burden of TB disproportionately. Once infected, children are not only more susceptible to TB than adults, but also are more likely to develop a severe form of the disease. Specifically, following infection more than 90% of immunocompetent adults will establish an asymptomatic, latent TB infection (LTBI), which carries a 5–10% life-time risk of reactivation disease. Whereas, in the majority of young infants, a primary Mtb infection will advance to active TB, and then in a substantial proportion of those with active TB, the disease will progress to a more severe form (e.g., miliary TB). In addition to an increased susceptibility to TB, prompt diagnosis in children is complicated by the fact that children with progressive primary infections seldom present with a positive sputum acid-fast bacillus smear, which is commonly seen in adult pulmonary reactivation disease. Early detection is essential since progression of the disease occurs during the period of diagnostic delay. Understanding the basis for the increased susceptibility of children to developing TB is likely to lead to improved vaccines and immunodiagnostics.

Numerous studies in animal models and Mtb-infected adults have established innate and adaptive cellular immunity as playing an important role in preventing Mtb infection (2). The activated macrophage, which also is chief host cell for Mtb, serves as the first line of defense but is not sufficient for control of bacterial replication. Rather, containment depends on the priming of effective adaptive T cell responses by dendritic cells (DC). Studies using the murine TB model have established that CD4+ TH1 cells and CD8+ T cells, which produce IFN-γ and TNF-α and are cytolytic, are essential for host defense. In humans, healthy adults with LTBI demonstrate strong IFN-γ producing T cell responses, whereas individuals immunocompromised by AIDS, or rare IFN-γ receptor deficiencies, demonstrate increased susceptibility to TB. Furthermore, in adults, regulatory T cells have been shown to be associated with pulmonary TB, and CD4+ TH2 cells, producing IL-4, IL-5, and/or IL-13, may be associated with more severe TB.

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