Tamm-Horsfall glycoprotein links innate immune cell activation with adaptive immunity via a Toll-like receptor-4–dependent mechanism
Marcus D. Säemann, Thomas Weichhart, Maximilian Zeyda, Günther Staffler, Michael Schunn, Karl M. Stuhlmeier, Yuri Sobanov, Thomas M. Stulnig, Shizuo Akira, Alexander von Gabain, Uwe von Ahsen, Walter H. Hörl, Gerhard J. Zlabinger
Marcus D. Säemann, Thomas Weichhart, Maximilian Zeyda, Günther Staffler, Michael Schunn, Karl M. Stuhlmeier, Yuri Sobanov, Thomas M. Stulnig, Shizuo Akira, Alexander von Gabain, Uwe von Ahsen, Walter H. Hörl, Gerhard J. Zlabinger
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Article Immunology

Tamm-Horsfall glycoprotein links innate immune cell activation with adaptive immunity via a Toll-like receptor-4–dependent mechanism

Abstract

Tamm-Horsfall glycoprotein (THP) is expressed exclusively in the kidney and constitutes the most abundant protein in mammalian urine. A critical role for THP in antibacterial host defense and inflammatory disorders of the urogenital tract has been suggested. We demonstrate that THP activates myeloid DCs via Toll-like receptor-4 (TLR4) to acquire a fully mature DC phenotype. THP triggers typical TLR signaling, culminating in activation of NF-κB. Bone marrow–derived macrophages from TLR4- and MyD88-deficient mice were nonresponsive to THP in contrast to those from TLR2- and TLR9-deficient mice. In vivo THP-driven TNF-α production was evident in WT but not in Tlr4–/– mice. Importantly, generation of THP-specific Abs consistently detectable in urinary tract inflammation was completely blunted in Tlr4–/– mice. These data show that THP is a regulatory factor of innate and adaptive immunity and therefore could have significant impact on host immunity in the urinary tract.

Authors

Marcus D. Säemann, Thomas Weichhart, Maximilian Zeyda, Günther Staffler, Michael Schunn, Karl M. Stuhlmeier, Yuri Sobanov, Thomas M. Stulnig, Shizuo Akira, Alexander von Gabain, Uwe von Ahsen, Walter H. Hörl, Gerhard J. Zlabinger

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Induction of T cell stimulatory capacity and type 1 immune responsivenes...
Induction of T cell stimulatory capacity and type 1 immune responsiveness by THP. (A) Immature human monocyte-derived DCs were stimulated with THP or LPS, washed extensively, irradiated, and subsequently cocultured with highly purified allogeneic T cells at the indicated ratios. After 48 hours, the cells were used as allogeneic stimulators as described above. DNA synthesis was assessed on day 5 and is expressed as mean counts per minute of a representative experiment. SD of triplicates were generally below 20%. Similar results were obtained in 4 other experiments. (B) For T cell cytokine production, immature DCs were stimulated with THP at the indicated concentrations or LPS, extensively washed, irradiated, and subsequently cocultured with highly purified allogeneic T cells at a DC/T cell ratio of 1:2. Cell-free supernatants were collected and analyzed by ELISA for IL-2 and IFN-γ secretion. Data are expressed as mean ± SEM of 4 different donor combinations.