title: Protein kinase C signaling during T cell activation induces the endoplasmic reticulum stress response.
abstract: T cell receptor (TCR) ligation (signal one) in the presence of co-stimulation (signal two) results in downstream signals that increase protein production enabling naïve T cells to fully activate and gain effector function. Enhanced production of proteins by a cell requires an increase in endoplasmic reticulum (ER) chaperone expression, which is accomplished through activation of a cellular mechanism known as the ER stress response. The ER stress response is initiated during the cascade of events that occur for the activation of many cells; however, this process has not been comprehensively studied for T cell function. In this study, we used primary T cells and mice circulating TCR transgenic CD8(+) T cells to investigate ER chaperone expression in which TCR signaling was initiated in the presence or absence of co-stimulation. In the presence of both signals, in vitro and in vivo analyses demonstrated induction of the ER stress response, as evidenced by elevated expression of GRP78 and other ER chaperones. Unexpectedly, ER chaperones were also increased in T cells exposed only to signal one, a treatment known to cause T cells to enter the 'nonresponsive' states of anergy and tolerance. Treatment of T cells with an inhibitor to protein kinase C (PKC), a serine/threonine protein kinase found downstream of TCR signaling, indicated PKC is involved in the induction of the ER stress response during the T cell activation process, thus revealing a previously unknown role for this signaling protein in T cells. Collectively, these data suggest that induction of the ER stress response through PKC signaling is an important component for the preparation of a T cell response to antigen.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, MA 01605, USA.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Pino
authors.forename: Bryan
authors.initials: B
authors.lastname: O'Sullivan-Murphy
authors.forename: Erich A
authors.initials: EA
authors.lastname: Lidstone
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Thornley
authors.forename: Agata
authors.initials: A
authors.lastname: Jurczyk
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Urano
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
authors.forename: John P
authors.initials: JP
authors.lastname: Mordes
authors.forename: Aldo A
authors.initials: AA
authors.lastname: Rossini
authors.forename: Rita
authors.initials: R
authors.lastname: Bortell
mesh_terms: D000818:Animals; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000201:enzymology*; D000091342:Endoplasmic Reticulum Chaperone BiP; D004789:Enzyme Activation / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000378:metabolism; D007108:Immune Tolerance / Q000187:drug effects; D007376:Interleukin-2 / Q000096:biosynthesis; D015759:Ionomycin / Q000494:pharmacology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008297:Male; D051379:Mice; D008954:Models, Biological; D018832:Molecular Chaperones / Q000378:metabolism; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000201:enzymology* / Q000276:immunology*; D019284:Thapsigargin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; C000717248:Hspa5 protein, mouse; D007376:Interleukin-2; D018832:Molecular Chaperones; D047428:Protein Kinase Inhibitors; D011948:Receptors, Antigen, T-Cell; D015240:Phorbol 12,13-Dibutyrate; D015759:Ionomycin; D019284:Thapsigargin; D011493:Protein Kinase C