WSX-1 signalling inhibits CD4+ T cell migration to the liver during malaria infection by repressing chemokine-independent pathways

Ana Villegas-Mendez, Emily Gwyer Findlay, J. Brian De Souza, Lisa Marie Grady, Christiaan J. Saris, Thomas E. Lane, Eleanor M. Riley, Kevin N. Couper

    Research output: Contribution to journalArticlepeer-review

    Abstract

    IL-27 is an important and non-redundant regulator of effector T cell accumulation in non-lymphoid tissues during infection. Using malaria as a model systemic pro-inflammatory infection, we demonstrate that the aberrant accumulation of CD4+ T cells in the liver of infected IL27R -/- (WSX-1-/-) mice is a result of differences in cellular recruitment, rather than changes in T cell proliferation or cell death. We show that IL-27 both inhibits the migratory capacity of infection-derived CD4 + T cells towards infection-derived liver cells, but also suppresses the production of soluble liver-derived mediator(s) that direct CD4+ T cell movement towards the inflamed tissue. Although CCL4 and CCL5 expression was higher in livers of infected WSX-1-/- mice than infected WT mice, and hepatic CD4+ T cells from WSX-1-/- mice expressed higher levels of CCR5 than cells from WT mice, migration of CD4+ T cells to the liver of WSX-1-/- mice during infection was not controlled by chemokine (R) signalling. However, anti-IL-12p40 treatment reduced migration of CD4+ T cells towards infection-derived liver cells, primarily by abrogating the hepatotropic migratory capacity of T cells, rather than diminishing soluble tissue-derived migratory signals. These results indicate that IL-27R signalling restricts CD4+ T cell accumulation within the liver during infection primarily by suppressing T cell chemotaxis, which may be linked to its capacity to repress Th1 differentiation, as well as by inhibiting the production of soluble, tissue-derived chemotaxins. © 2013 Villegas-Mendez et al.
    Original languageEnglish
    Article numbere78486
    JournalPLoS ONE
    Volume8
    Issue number11
    DOIs
    Publication statusPublished - 7 Nov 2013

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