Academic Journal
A role for mammalian target of rapamycin in regulating T cell activation versus anergy.
| Τίτλος: | A role for mammalian target of rapamycin in regulating T cell activation versus anergy. |
|---|---|
| Συγγραφείς: | Zheng Y; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University Medical Institutions, Baltimore, MD 21231, USA., Collins SL, Lutz MA, Allen AN, Kole TP, Zarek PE, Powell JD |
| Πηγή: | Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2007 Feb 15; Vol. 178 (4), pp. 2163-70. |
| Τύπος έκδοσης: | Journal Article; Research Support, N.I.H., Extramural |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Oxford University Press Country of Publication: England NLM ID: 2985117R Publication Model: Print Cited Medium: Print ISSN: 0022-1767 (Print) Linking ISSN: 00221767 NLM ISO Abbreviation: J Immunol Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2025- : [Oxford] : Oxford University Press Original Publication: Baltimore : Williams & Wilkins, c1950- |
| Ιατρικοί όροι (MeSH): | Clonal Anergy/*drug effects , Immunosuppressive Agents/*pharmacology , Lymphocyte Activation/*drug effects , Protein Kinases/*immunology , Sirolimus/*pharmacology , T-Lymphocytes/*immunology, Antigen Presentation/drug effects ; Antigens, CD/biosynthesis ; Antigens, CD/immunology ; Gene Expression Regulation/drug effects ; Gene Expression Regulation/immunology ; Lymphocyte Activation/immunology ; Protein Kinases/metabolism ; Receptors, Transferrin/biosynthesis ; Receptors, Transferrin/immunology ; Ribosomal Protein S6 Kinases/immunology ; Ribosomal Protein S6 Kinases/metabolism ; T-Lymphocytes/enzymology ; Animals ; Humans ; Jurkat Cells ; Mice ; TOR Serine-Threonine Kinases |
| Περίληψη: | Whether TCR engagement leads to activation or tolerance is determined by the concomitant delivery of multiple accessory signals, cytokines, and environmental cues. In this study, we demonstrate that the mammalian target of rapamycin (mTOR) integrates these signals and determines the outcome of TCR engagement with regard to activation or anergy. In vitro, Ag recognition in the setting of mTOR activation leads to full immune responses, whereas recognition in the setting of mTOR inhibition results in anergy. Full T cell activation is associated with an increase in the phosphorylation of the downstream mTOR target S6 kinase 1 at Thr(421)/Ser(424) and an increase in the mTOR-dependent cell surface expression of transferrin receptor (CD71). Alternatively, the induction of anergy results in markedly less S6 kinase 1 Thr(421)/Ser(424) phosphorylation and CD71 surface expression. Likewise, the reversal of anergy is associated not with proliferation, but rather the specific activation of mTOR. Importantly, T cells engineered to express a rapamycin-resistant mTOR construct are resistant to anergy induction caused by rapamycin. In vivo, mTOR inhibition promotes T cell anergy under conditions that would normally induce priming. Furthermore, by examining CD71 surface expression, we are able to distinguish and differentially isolate anergic and activated T cells in vivo. Overall, our data suggest that by integrating environmental cues, mTOR plays a central role in determining the outcome of Ag recognition. |
| Grant Information: | 5K22AI1773 United States AI NIAID NIH HHS; R01CA98109 United States CA NCI NIH HHS |
| Substance Nomenclature: | 0 (Antigens, CD) 0 (CD71 antigen) 0 (Immunosuppressive Agents) 0 (Receptors, Transferrin) EC 2.7.- (Protein Kinases) EC 2.7.1.1 (MTOR protein, human) EC 2.7.1.1 (mTOR protein, mouse) EC 2.7.11.1 (Ribosomal Protein S6 Kinases) EC 2.7.11.1 (TOR Serine-Threonine Kinases) W36ZG6FT64 (Sirolimus) |
| Entry Date(s): | Date Created: 20070206 Date Completed: 20070320 Latest Revision: 20211203 |
| Update Code: | 20260130 |
| DOI: | 10.4049/jimmunol.178.4.2163 |
| PMID: | 17277121 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 0022-1767 |
|---|---|
| DOI: | 10.4049/jimmunol.178.4.2163 |