Cutting edge: Genetic variation in TLR1 is associated with Pam3CSK4-induced effector T cell resistance to regulatory T cell suppression.
TLR play essential roles in the initiation and modulation of immune responses. TLR1/TLR2 heterodimers recognize triacylated bacterial lipopeptides, including the synthetic TLR1/2 lipopeptide Pam3CSK4. Genetic variation in TLR1 is associated with outcomes in diseases in which regulatory T cells (Treg) play a role, including asthma and allergy. To determine whether genetic polymorphisms in TLR1 are associated with alterations in Treg suppression of effector T cells (Teff), we performed in vitro suppression assays in healthy individuals with various haplotypes in TLR1. We show that functional genetic polymorphisms in TLR1 modify surface expression of TLR1 on T lymphocytes and confer enhanced Teff resistance to Treg suppression in the presence of Pam3CSK4. These effects are mediated, in part, by IL-6 and inhibited by blocking IL-6 signaling through STAT3. These findings suggest that TLR1 polymorphisms could influence immune-related disease through Teff resistance to Treg suppression.
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle, WA 98104; and cmikacen@uw.edu.
Carmen
http://orcid.org/0000-0001-8966-5161
C
Mikacenic
Translational Research Program, Benaroya Research Institute, Seattle, WA 98101.
Anya
A
Schneider
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle, WA 98104; and.
Frank
F
Radella
Translational Research Program, Benaroya Research Institute, Seattle, WA 98101.
Jane H
JH
Buckner
Division of Pulmonary and Critical Care Medicine, Department of Medicine, University of Washington, Seattle, WA 98104; and.
Mark M
MM
Wurfel
D000483:Alleles; D002462:Cell Membrane / Q000378:metabolism; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D056747:Immunomodulation / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis; D055666:Lipopeptides / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D051194:Toll-Like Receptor 1 / Q000235:genetics* / Q000378:metabolism*
D015850:Interleukin-6; D055666:Lipopeptides; C508075:Pam(3)CSK(4) peptide; D050796:STAT3 Transcription Factor; D051194:Toll-Like Receptor 1