TLR7 induces anergy in human CD4(+) T cells.
The recognition of microbial patterns by Toll-like receptors (TLRs) is critical for activation of the innate immune system. Although TLRs are expressed by human CD4(+) T cells, their function is not well understood. Here we found that engagement of TLR7 in CD4(+) T cells induced intracellular calcium flux with activation of an anergic gene-expression program dependent on the transcription factor NFATc2, as well as unresponsiveness of T cells. As chronic infection with RNA viruses such as human immunodeficiency virus type 1 (HIV-1) induces profound dysfunction of CD4(+) T cells, we investigated the role of TLR7-induced anergy in HIV-1 infection. Silencing of TLR7 markedly decreased the frequency of HIV-1-infected CD4(+) T cells and restored the responsiveness of those HIV-1(+) CD4(+) T cells. Our results elucidate a previously unknown function for microbial pattern-recognition receptors in the downregulation of immune responses.
Department of Neurology and Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA.
Margarita
M
Dominguez-Villar
Department of Neurology and Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA.
Anne-Sophie
AS
Gautron
Department of Neurology and Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA.
Marine
M
de Marcken
Albert Einstein College of Medicine and Montefiore Medical Center, Bronx, New York, USA.
Marla J
MJ
Keller
Department of Neurology and Department of Immunobiology, Yale School of Medicine, New Haven, Connecticut, USA.
David A
DA
Hafler
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D002118:Calcium / Q000276:immunology; D017635:Clonal Anergy / Q000276:immunology; D015536:Down-Regulation; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000276:immunology; D008213:Lymphocyte Activation; D050778:NFATC Transcription Factors / Q000276:immunology; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D051199:Toll-Like Receptor 7 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology*
D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D034741:RNA, Small Interfering; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D002118:Calcium