Human regulatory T cells induce T-lymphocyte senescence.
Regulatory T (Treg) cells have broad suppressive activity on host immunity, but the fate and function of suppressed responder T cells remains largely unknown. In the present study, we report that human Treg cells can induce senescence in responder naive and effector T cells in vitro and in vivo. Senescent responder T cells induced by human Treg cells changed their phenotypes and cytokine profiles and had potent suppressive function. Furthermore, Treg-mediated molecular control of senescence in responder T cells was associated with selective modulation of p38 and ERK1/2 signaling and cell-cycle-regulatory molecules p16, p21, and p53. We further revealed that human Treg-induced senescence and suppressor function could be blocked by TLR8 signaling and/or by specific ERK1/2 and p38 inhibition in vitro and in vivo in animal models. The results of the present study identify a novel mechanism of human Treg cell suppression that induces targeted responder T-cell senescence and provide new insights relevant for the development of strategies capable of preventing and/or reversing Treg-induced immune suppression.
Division of Infectious Diseases, Allergy & Immunology and Department of Internal Medicine, St Louis University School of Medicine, St Louis, MO 63104, USA.
Jian
J
Ye
Xingxu
X
Huang
Eddy C
EC
Hsueh
Qunyuan
Q
Zhang
Chunling
C
Ma
Yanping
Y
Zhang
Mark A
MA
Varvares
Daniel F
DF
Hoft
Guangyong
G
Peng
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002450:Cell Communication / Q000276:immunology; D002453:Cell Cycle / Q000276:immunology; D016922:Cellular Senescence / Q000276:immunology*; D018920:Coculture Techniques; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D015870:Gene Expression / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate; D008213:Lymphocyte Activation; D020935:MAP Kinase Signaling System / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology; D061251:Primary Cell Culture; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D051200:Toll-Like Receptor 8 / Q000235:genetics / Q000276:immunology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000276:immunology
C493956:CDKN1A protein, human; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016207:Cytokines; D009363:Neoplasm Proteins; C495349:TLR8 protein, human; D051200:Toll-Like Receptor 8; D016159:Tumor Suppressor Protein p53