Article

Functional Specializations of Intestinal Dendritic Cell and Macrophage Subsets That Control Th17 and Regulatory T Cell Responses Are Dependent on the T Cell/APC Ratio, Source of Mouse Strain, and Regional Localization

Vaccine Research Center, Emory University, Atlanta, GA 30329, USA.
The Journal of Immunology (Impact Factor: 4.92). 06/2011; 187(2):733-47. DOI: 10.4049/jimmunol.1002701
Source: PubMed

ABSTRACT

Although several subsets of intestinal APCs have been described, there has been no systematic evaluation of their phenotypes, functions, and regional localization to date. In this article, we used 10-color flow cytometry to define the major APC subsets in the small and large intestine lamina propria. Lamina propria APCs could be subdivided into CD11c(+)CD11b(-), CD11c(+)CD11b(+), and CD11c(dull)CD11b(+) subsets. CD11c(+)CD11b(-) cells were largely CD103(+)F4/80(-) dendritic cells (DCs), whereas the CD11c(+)CD11b(+) subset comprised CD11c(+)CD11b(+)CD103(+)F4/80(-) DCs and CD11c(+)CD11b(+)CD103(-)F4/80(+) macrophage-like cells. The majority of CD11c(dull)CD11b(+) cells were CD103(-)F4/80(+) macrophages. Although macrophages were more efficient at inducing Foxp3(+) regulatory T (T(reg)) cells than DCs, at higher T cell/APC ratios, all of the DC subsets efficiently induced Foxp3(+) T(reg) cells. In contrast, only CD11c(+)CD11b(+)CD103(+) DCs efficiently induced Th17 cells. Consistent with this, the regional distribution of CD11c(+)CD11b(+)CD103(+) DCs correlated with that of Th17 cells, with duodenum > jejunum > ileum > colon. Conversely, CD11c(+)CD11b(-)CD103(+) DCs, macrophages, and Foxp3(+) T(reg) cells were most abundant in the colon and scarce in the duodenum. Importantly, however, the ability of DC and macrophage subsets to induce Foxp3(+) T(reg) cells versus Th17 cells was strikingly dependent on the source of the mouse strain. Thus, DCs from C57BL/6 mice from Charles River Laboratories (that have segmented filamentous bacteria, which induce robust levels of Th17 cells in situ) were more efficient at inducing Th17 cells and less efficient at inducing Foxp3(+) T(reg) cells than DCs from B6 mice from The Jackson Laboratory. Thus, the functional specializations of APC subsets in the intestine are dependent on the T cell/APC ratio, regional localization, and source of the mouse strain.

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    • "Intuitively , the GM of research animals can similarly affect the phenotype of models of human disease. While this has been recognized anecdotally for many years, only recently have reports appeared in the literature with substantive data to support this hypothesis (Denning et al. 2011; Ivanov et al. 2008; Robosky et al. 2005; Rohde et al. 2007; Yang et al. 2013). Frequently, an investigator will experience a loss or change in phenotype when an animal colony is relocated to a different institution or undergoes a change in husbandry. "
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    ABSTRACT: Eukaryotic organisms are colonized by rich and dynamic communities of microbes, both internally (e.g., in the gastrointestinal and respiratory tracts) and externally (e.g., on skin and external mucosal surfaces). The vast majority of bacterial microbes reside in the lower gastrointestinal (GI) tract, and it is estimated that the gut of a healthy human is home to some 100 trillion bacteria, roughly an order of magnitude greater than the number of host somatic cells. The development of culture-independent methods to characterize the gut microbiota (GM) has spurred a renewed interest in its role in host health and disease. Indeed, associations have been identified between various changes in the composition of the GM and an extensive list of diseases, both enteric and systemic. Animal models provide a means whereby causal relationships between characteristic differences in the GM and diseases or conditions can be formally tested using genetically identical animals in highly controlled environments. Clearly, the GM and its interactions with the host and myriad environmental factors are exceedingly complex, and it is rare that a single microbial taxon associates with, much less causes, a phenotype with perfect sensitivity and specificity. Moreover, while the exact numbers are the subject of debate, it is well recognized that only a minority of gut bacteria can be successfully cultured ex vivo. Thus, to perform studies investigating causal roles of the GM in animal model phenotypes, researchers need clever techniques to experimentally manipulate the GM of animals, and several ingenious methods of doing so have been developed, each providing its own type of information and with its own set of advantages and drawbacks. The current review will focus on the various means of experimentally manipulating the GM of research animals, drawing attention to the factors that would aid a researcher in selecting an experimental approach, and with an emphasis on mice and rats, the primary model species used to evaluate the contribution of the GM to a disease phenotype. © The Author 2015. Published by Oxford University Press on behalf of the Institute for Laboratory Animal Research. All rights reserved. For permissions, please email: journals.permissions@oup.com.
    Full-text · Article · Aug 2015 · ILAR journal / National Research Council, Institute of Laboratory Animal Resources
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    • "The role of MNP subsets in LP Th17 cell induction in vivo is unclear . Previous studies have proposed either LP DCs or Mfs as mediators of Th17 cell induction (Atarashi et al., 2008; Denning et al., 2011; Scott et al., 2015). However, this was largely based on assessing the ability of isolated MNP subsets to skew T cell differentiation in vitro, and their differential roles under physiological conditions are not clear. "
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    ABSTRACT: Graphical Abstract Highlights d Intestinal CD103 DCs are dispensable for induction of Th17 cells by a gut commensal d Intestinal CX3CR1 macrophages are required for Th17 cell induction by SFB d Intestinal CX3CR1 macrophages are required for a commensal antigen-specific response
    Full-text · Article · Aug 2015
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    • "The role of MNP subsets in LP Th17 cell induction in vivo is unclear . Previous studies have proposed either LP DCs or Mfs as mediators of Th17 cell induction (Atarashi et al., 2008; Denning et al., 2011; Scott et al., 2015). However, this was largely based on assessing the ability of isolated MNP subsets to skew T cell differentiation in vitro, and their differential roles under physiological conditions are not clear. "
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