Abstract
Production of innate interferon-γ (IFN-γ) is a crucial step in immunological defense against bacteria. However, there is little information regarding cellular mechanisms underlying IFN-γ production in vivo early after bacterial infection. Here we analyze innate IFN-γ production in the spleen of mice early after Listeria monocytogenes (LM) infection ex vivo by flow-cytometry and in situ by immunohistochemistry, and compare them with the IFN-γ-producing cells reported previously in our in vitro coculture system in which cell-cell interaction between lymphocytes and dying bacterial-infected macrophages is required for the production of IFN-γ. In the spleen at 20 h after LM infection, natural killer (NK) cells, a subset of αβ T cells, and subsets of NKT and γδ T cells produced IFN-γ with features similar to the IFN-γ-producing cells in our in vitro coculture system. Immunohistochemistry revealed that LM bacteria were first phagocytosed mainly by ER-TR9+ marginal zone macrophages (MZMs), then forming infectious foci in close vicinity of the marginal zone (MZ) at 20-h postinfection. At this time point, the IFN-γ-producing cells were accumulating at the same site of infectious foci, around which ER-TR9+ MZMs were clustered but most of bacteria were no longer associated with ER-TR9+ MZMs. These results indicate that innate IFN-γ production by innate lymphocytes takes place at infectious foci formed in close vicinity of the MZ, and they also suggest an important role for the microenvironment of the cells accumulated at infectious foci in inducing the production of innate IFN-γ.
Highlights
Listeria monocytogenes (LM) is a Gram-positive facultative intracellular bacterium that causes severe disseminated infection or local infection like meningitis in immunocompromised individuals and in pregnant women (Vazquez-Boland et al, 2001)
As we have recently shown by using an in vitro coculture system that subsets of Natural killer (NK), NKT, and γδ T cells, which are generically referred to as innate lymphocytes (Bendelic et al, 2001), produce IFN-γ in a cell–cell contact dependent manner in response to dying bacterialinfected macrophages (Kubota, 2006) and have proposed that this IFN-γ production pathway contributes to the host defense at the initial phase of bacterial infection (Kubota, 2010), we compare the innate IFN-γ-producing cells in the LM-infected spleen with the IFN-γ-producing cells in our in vitro coculture system to explore the relevance of our in vitro finding to the in vivo situation in the spleen early after LM infection
We revealed in this study that early after LM infection, NK cells and, to a lesser extent, a subset of αβ T cells, subsets of NKT and γδ T cells are the cellular sources of innate IFN-γ, and that LM bacteria are first phagocytosed by marginal zone macrophages (MZMs), forming infectious foci in close vicinity of the marginal zone (MZ) without being associated with MZMs at 20-h postinfection, and that the innate IFN-γ-producing cells form cell clusters at the same site of infectious foci
Summary
Listeria monocytogenes (LM) is a Gram-positive facultative intracellular bacterium that causes severe disseminated infection or local infection like meningitis in immunocompromised individuals and in pregnant women (Vazquez-Boland et al, 2001). During an early stage of LM infection innate immune responses control initial infection, and subsequently T helper type 1 (Th1) adaptive immune responses develop to sterilize LM-infected mice (Unanue, 1997). Natural killer (NK) cells are thought to be the main source of innate IFN-γ, but other multiple cell types, such as memory type CD8+ T cells, NKT cells, γδT cells, macrophages, and dendritic cells (DCs) are claimed to produce innate IFN-γ (Hiromatsu et al, 1992; Bancroft, 1993; Frucht et al, 2001; Berg et al, 2005; Berntman et al, 2005; Thale and Kiderlen, 2005). NK1.1+CD11c+ cells have recently been reported to be the primary IFN-γ-producing cells in the spleen early after LM infection in mice (Chang et al, 2007; Plitas et al, 2007). The cellular sources of innate IFN-γ remain still unsettled
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