Editors' ChoiceIMMUNITY

The Lymph Node Labyrinth

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Science Translational Medicine  26 Sep 2012:
Vol. 4, Issue 153, pp. 153ec175
DOI: 10.1126/scitranslmed.3004990

The Labyrinth of Greek mythology was a supposedly inescapable maze designed to imprison the half-man, half-bull Minotaur. Indeed, it was believed that the complex structure of the maze was integral to its function. Now, researchers have demonstrated that the lymph node may serve as a Labyrinth to entrap pathogens and that its structural cellular orientation is crucial to its function during host defense.

Lymph nodes are organs that optimize adaptive immune responses. However, lymphatics can be hijacked by pathogens to gain entry to the blood before adaptive immune responses take effect. Kastenmüller et al. used confocal immunofluorescence and intravital two-photon microscopy to investigate how lymph node cellular structure contributes to pathogen capture and killing in mice. The investigators demonstrated that both virus and bacteria could gain entry into the lymphatics after skin inoculation, but once they entered the lymph node, there was no escape. Prepositioned subcapsular sinus macrophages stood guard at lymphatic entry points, immediately trapping incoming microbes. Chemical depletion of these macrophages resulted in pathogen escape and dissemination into the blood stream. Aiding these sentinel macrophages were a group of innate lymphocytes composed of natural killer (NK) cells, NK T cells, and innate-like CD8+ T cells. A reciprocating relationship existed in which pathogen activated macrophages released inflammasome-generated interleukin-18 (IL-18), promoting interferon-γ release from the innate lymphocytes, which in turn acted on macrophages to increase pathogen-killing ability. To ensure that no pathogen escaped, macrophages released IL-1β, which rapidly recruited neutrophil reinforcements. Thus, the cellular orientation was critical to ensure that pathogens could not escape the lymph node once it was entered.

This study reveals that the lymph node actively participates in acute host defense and that its cellular structure is predetermined in order to efficiently capture pathogens as well as to facilitate cellular communication. Currently, these complex interactions cannot be fully investigated in humans; however, understanding the mechanisms guiding cellular spatial orientation provides a new layer of potential targets to manipulate and enhance the immune response.

W. Kastenmüller et al., A spatially-organized multicellular innate immune response in lymph nodes limits systemic pathogen spread. Cell 14, 1235–1248 (2012). [Abstract]

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