A novel complement-mediated pathway for human T(H)2 induction via direct epithelial cell/T cell crosstalk

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Abstract

Complement plays vital roles in shaping adaptive B and T cell responses. Particularly, the direct regulation of TH1 responses by complement activation fragment signalling via their receptors on T cell is now solidly recognized. Although it is clear that complement deregulation participates in the induction and progression of TH2-driven disease states, such as asthma, the underlying mechanisms are less defined. Because of complement's role as defence system particularly at the host/environment interface, we hypothesized that complement may regulate TH2 responses via a previously unappreciated axis, i.e. the direct crosstalk between epithelial cells and T cells. We found that the anaphylatoxin C5a leads to secretion of the two TH2 response-inducing cytokines Thymic Stromal Lymphopoietin (TSLP) and IL-25 in a dose-dependent manner by human lung epithelial cells (LECs). In addition to this direct stimulatory effect, C5a negatively regulated Toll-like receptor (TLR)-induced TSLP production by LECs. In contrast, C5a did not induce or modulate the secretion of GM-CSF or IL-33, two additional cytokines supporting TH2 induction. Importantly, supernatants from C5a-treated LECs also induced TH2 responses and suppressed TH1 responses when applied to human CD4+ T cells during activation. These results suggest that complement can induce TH2 responses through a novel pathway, in which the C5a:C5a receptor axis regulates TSLP production by a direct epithelial cell/T cell crosstalk. Targeting this pathway may be a strategy for therapeutic intervention. In addition, our finding that C5a negatively regulates TLR-mediated TSLP production could explain the opposing effects of this molecule during the initiation and effector phases of asthma. Excitingly, we have observed a similar TSLP-regulative phenotype for C5a in mouse LECs and are currently addressing the in vivo importance of this finding in a mouse model of asthma.
Original languageEnglish
Pages (from-to)1219-1220
Number of pages2
JournalImmunobiology
Volume217
Issue number11
DOIs
Publication statusPublished - Nov 2012

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