Human CD4+ T Cells Express TLR5 and Its Ligand Flagellin Enhances the Suppressive Capacity and Expression of FOXP3 in CD4+CD25+ T Regulatory Cells

• Published in: The Journal of immunology (1950) 2005-12, Vol.175 (12), p.8051-8059
• Main Authors: Crellin, Natasha K, Garcia, Rosa V, Hadisfar, Omeed, Allan, Sarah E, Steiner, Theodore S, Levings, Megan K
• Format: Article
• Language: English
• Subjects: Antibodies, Monoclonal - pharmacology; CD3 Complex - immunology; CD4-Positive T-Lymphocytes - chemistry; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - physiology; Flagellin - pharmacology; Forkhead Transcription Factors - genetics; Humans; Interleukin-2 - biosynthesis; Receptors, Interleukin-2; T-Lymphocytes, Regulatory - chemistry; T-Lymphocytes, Regulatory - drug effects; T-Lymphocytes, Regulatory - metabolism; Toll-Like Receptor 5 - analysis; Toll-Like Receptor 5 - physiology; Up-Regulation - drug effects
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.175.12.8051

Germline encoded pattern recognition receptors, such as TLRs, provide a critical link between the innate and adaptive immune systems. There is also evidence to suggest that pathogen-associated molecular patterns may have the capacity to modulate immune responses via direct effects on CD4+ T cells. Given the key role of both CD4+CD25+ T regulatory (Treg) cells and the TLR5 ligand flagellin in regulating mucosal immune responses, we investigated whether TLR5 may directly influence T cell function. We found that both human CD4+CD25+ Treg and CD4+CD25- T cells express TLR5 at levels comparable to those on monocytes and dendritic cells. Costimulation of effector T cells with anti-CD3 and flagellin resulted in enhanced proliferation and production of IL-2, at levels equivalent to those achieved by costimulation with CD28. In contrast, costimulation with flagellin did not break the hyporesponsiveness of CD4+CD25+ Treg cells, but rather, potently increased their suppressive capacity and enhanced expression of FOXP3. These observations suggest that, in addition to their APC-mediated indirect effects, TLR ligands have the capacity to directly regulate T cell responses and modulate the suppressive activity of Treg cells.