Abstract
Cellular immunity to Mycobacterium tuberculosis (Mtb) requires a coordinated response between the innate and adaptive arms of the immune system, resulting in a type 1 cytokine response, which is associated with control of infection. The contribution of innate lymphocytes to immunity against Mtb remains controversial. We established an in vitro system to study this question. Interferon-γ is produced when splenocytes from uninfected mice are cultured with Mtb-infected macrophages, and, under these conditions, bacterial replication is suppressed. This innate control of bacterial replication is dependent on CD1d-restricted invariant NKT (iNKT) cells, and their activation requires CD1d expression by infected macrophages as well as IL-12 and IL-18. We show that iNKT cells, even in limiting quantities, are sufficient to restrict Mtb replication. To determine whether iNKT cells contribute to host defense against tuberculosis in vivo, we adoptively transferred iNKT cells into mice. Primary splenic iNKT cells obtained from uninfected mice significantly reduce the bacterial burden in the lungs of mice infected with virulent Mtb by the aerosol route. Thus, iNKT cells have a direct bactericidal effect, even in the absence of synthetic ligands such as α-galactosylceramide. Our finding that iNKT cells protect mice against aerosol Mtb infection is the first evidence that CD1d-restricted NKT cells mediate protection against Mtb in vivo.
Highlights
Cells of the innate immune system use several receptor systems to recognize pathogens and act as the first line of defense against infection
By fractionating the different splenocyte cell populations, we discovered that the invariant NKT cell is essential for suppressing intracellular bacterial replication. iNKT cells, which are conserved in rodents and humans, recognize lipids presented by the antigen-presenting molecule CD1d
While we had previously shown that iNKT celldeficient mice are not more susceptible to tuberculosis, a potential contribution of iNKT cells during the early phase of immunity may have been masked
Summary
Cells of the innate immune system use several receptor systems to recognize pathogens and act as the first line of defense against infection. The expression of clonal antigen receptors and the capacity to differentiate into memory cells distinguish B and T lymphocytes as the central components of the adaptive immune system. Certain T subsets, such as cd T cells and NKT cells, have features of innate immune cells including a partially activated phenotype, a rapid response following detection of infected cells, and the modulation of other cell types [1]. While innate lymphocytes serve important roles in host resistance to different infections, it remains controversial whether these cells contribute to immunity against Mycobacterium tuberculosis (Mtb) infection. Cd T cells are frequently activated by a variety of pathogens including Mtb [4]. Mice lacking cd T cells succumb more rapidly than control mice following intravenous challenge with virulent Mtb; such a difference has not been observed following infection by the aerosol route [5,6]
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