TLR5 functions as an endocytic receptor to enhance flagellin-specific adaptive immunity

• Published in: European journal of immunology 2011-01, Vol.41 (1), p.29-38
• Main Authors: Letran, Shirdi E, Lee, Seung-Joo, Atif, Shaikh M, Uematsu, Satoshi, Akira, Shizuo, McSorley, Stephen J
• Format: Article
• Language: English
• Subjects: Adaptive Immunity; Animals; Antigen Presentation - immunology; CD4+ T cells; CD4-Positive T-Lymphocytes - immunology; Cells, Cultured; Dendritic cells; Dendritic Cells - immunology; Endocytosis - immunology; Flagellin - immunology; Genes, MHC Class II - immunology; Immunoglobulin G - immunology; Lymphocyte Activation - immunology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Myeloid Differentiation Factor 88 - immunology; TLR; Toll-Like Receptor 5 - genetics; Toll-Like Receptor 5 - immunology
• ISSN: 0014-2980; 1521-4141
• DOI: 10.1002/eji.201040717

Innate immune activation via TLR induces dendritic cell maturation and secretion of inflammatory mediators, generating favorable conditions for naïve T-cell activation. Here, we demonstrate a previously unknown function for TLR5, namely that it enhances MHC class-II presentation of flagellin epitopes to CD4⁺ T cells and is required for induction of robust flagellin-specific adaptive immune responses. Flagellin-specific CD4⁺ T cells expanded poorly in TLR5-deficient mice immunized with flagellin, a deficiency that persisted even when additional TLR agonists were provided. Flagellin-specific IgG responses were similarly depressed in the absence of TLR5. In marked contrast, TLR5-deficient mice developed robust flagellin-specific T-cell responses when immunized with processed flagellin peptide. Surprisingly, the adaptor molecule Myd88 was not required for robust CD4⁺ T-cell responses to flagellin, indicating that TLR5 enhances flagellin-specific CD4⁺ T-cell responses in the absence of conventional TLR signaling. A requirement for TLR5 in generating flagellin-specific CD4⁺ T-cell activation was also observed when using an in vitro dendritic cell culture system. Together, these data uncover an Myd88-independent function for dendritic cell TLR5 in enhancing the presentation of peptides to flagellin-specific CD4⁺ T cells.