Graduation Year

2007

Document Type

Dissertation

Degree

Ph.D.

Degree Granting Department

Cancer Biology

Major Professor

Eduardo Martin Sotomayor, M.D.

Committee Member

Julie Djeu, Ph.D.

Committee Member

Thomas Guadagno, Ph.D.

Committee Member

Kenneth Wright, Ph.D.

Keywords

TLR5, Macrophages, Toll-like receptors, IL-10, DCs

Abstract

Toll-like receptors (TLRs) expressed by cells of the immune system play a central role in the generation of immune responses against pathogens. Following TLR ligation, both pro-inflammatory and anti-inflammatory mediators are produced in order to elicit an immune response that controls the microbial infection while limiting tissue damage. Among these mediators, the proinflammatory cytokine IL-12 and the anti-inflammatory cytokine IL-10 are known to play major roles. Here, we show that in vitro or in vivo stimulation with flagellin, the TLR5 ligand, does not result in IL-10 production. Furthermore flagellin inhibits IL-10 production by other specific TLR ligands at the protein and mRNA levels while increasing IL-12p70 production. Several studies have linked the activation of extracellular signal regulated kinases (ERKs) with IL-10 induction by TLRs. Our findings that LPS-induced ERK activation is significantly decreased in flagellin-treated macrophages suggest that this pathway might play a role in the inhibition of IL-10 production by flagellin. Flagellin-mediated IL-10 inhibition was not observed in cells that do not express TLR5 supporting that this effect is TLR5-dependent.Flagellin used as an adjuvant is capable of priming antigen specific T cell responses in an in vivo model of tolerance using high dose peptide. Furthermore, DCs differentiated in tolerogenic conditions (tolerogenic-DCs) express higher levels of TLR5 mRNA than standard BM-DCs and respond more vigorously to flagellin stimulation. Antigen presentation by LPS-matured tolerogenic-DCs results in the differentiation of IL-10 producing T cells with a Tr1-like phenotype. On the contrary, antigen presentation by tolerogenic-DCs that have been stimulated with flagellin results in the differentiation of a typical Th1 responseThis study provides a new insight of the role of flagellin recognition by TLR5 in shaping the immune response elicited by flagellated microorganisms.

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