Soluble HIV Tat protein removes the IL-7 receptor alpha-chain from the surface of resting CD8 T cells and targets it for degradation.
IL-7 signaling is essential to CD8 T cell development, activation, and homeostasis. We have previously shown decreased expression of the IL-7R alpha-chain (CD127) on CD8 T cells in HIV(+) patients and that this downregulation is mediated at least in part by the HIV Tat protein. We show in this study that CD127 has a prolonged t(1/2) in resting CD8 T cells and continuously recycles on and off the cell membrane. We also demonstrate soluble Tat protein significantly decreases the t(1/2) of CD127. Soluble Tat is taken up from the medium and accumulates in CD8 T cells with a peak of 6 h. Once inside the cell, Tat exits the endosomes during their normal acidification and enters the cytosol. Tat then translocates to the inner leaflet of the cell membrane, where it binds directly to the cytoplasmic tail of CD127, inducing receptor aggregation and internalization through a process dependent on microtubules. Tat appears to then target CD127 for degradation via the proteasome. By removing CD127 from the cell surface, the HIV Tat protein is thus able to reduce IL-7 signaling and impair CD8 T cell proliferation and function.
Faller
Elliott M
EM
Ottawa Hospital Research Institute.
Sugden
Scott M
SM
McVey
Mark J
MJ
Kakal
Juzer A
JA
MacPherson
Paul A
PA
D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D002462:Cell Membrane / Q000276:immunology* / Q000378:metabolism* / Q000821:virology; D002478:Cells, Cultured; D003513:Cycloheximide / Q000494:pharmacology; D015536:Down-Regulation / Q000276:immunology; D004705:Endocytosis; D011992:Endosomes / Q000276:immunology / Q000378:metabolism; D005089:Exocytosis / Q000276:immunology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015851:Interleukin-7 / Q000037:antagonists & inhibitors / Q000502:physiology; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D021381:Protein Transport / Q000276:immunology; D020395:Receptors, Interleukin-7 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000378:metabolism*; D016192:Resting Phase, Cell Cycle / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D012995:Solubility; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism / Q000502:physiology*
D015851:Interleukin-7; D021122:Protein Subunits; D011500:Protein Synthesis Inhibitors; D020395:Receptors, Interleukin-7; C415350:interleukin-7 receptor, alpha chain; D054322:tat Gene Products, Human Immunodeficiency Virus; D003513:Cycloheximide