title: Abundant expression of granzyme A, but not perforin, in granules of CD8+ T cells in GALT: implications for immune control of HIV-1 infection.
abstract: Because GALT is a major portal of entry for HIV-1 and reservoir for viral replication, we hypothesized that an ineffective cellular immune response in intestinal mucosa might partially explain the failure of immune control in AIDS. In this study, we demonstrate that the vast majority of CD8+ T cells in rectal tissue, including HIV-1-specific cells, fail to express the cytolytic protein, perforin. However, rectal CD8+ T cells do express granzyme A, and are also capable of releasing IFN-gamma upon stimulation with cognate peptide. Confocal microscopy showed that granzyme A was located in intracellular granules in the absence of perforin. The majority of rectal CD8+ T cells exhibit an effector memory phenotype, expressing CD45RO but not CCR7. Quantitative real-time PCR analysis demonstrated that perforin RNA is expressed in rectal CD8+ T cells from healthy and HIV-1-positive individuals. In HIV-1-positive individuals, similar amounts of perforin RNA were detected in CD8+ T cells from rectal tissue and PBMC, despite a relative absence of perforin protein in rectal tissue. These findings demonstrate an important difference in perforin expression between CD8+ T cells in blood and mucosa. Furthermore, the relative absence of armed effector cells may serve to protect the integrity of rectal mucosa under normal conditions, but might also provide an early advantage to HIV-1 and other sexually transmitted viruses.
authors.affiliation: Gladstone Institute of Virology and Immunology (GIVI), Department of Medicine, University of California-San Francisco, San Francisco, CA 94141, USA. blshacklett@ucdavis.edu
authors.forename: Barbara L
authors.initials: BL
authors.lastname: Shacklett
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Cox
authors.forename: Máire F
authors.initials: MF
authors.lastname: Quigley
authors.forename: Christophe
authors.initials: C
authors.lastname: Kreis
authors.forename: Neil H
authors.initials: NH
authors.lastname: Stollman
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jacobson
authors.forename: Jan
authors.initials: J
authors.lastname: Andersson
authors.forename: Johan K
authors.initials: JK
authors.lastname: Sandberg
authors.forename: Douglas F
authors.initials: DF
authors.lastname: Nixon
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology*; D000328:Adult; D018414:CD8-Positive T-Lymphocytes / Q000737:chemistry / Q000276:immunology*; D003594:Cytoplasmic Granules / Q000737:chemistry*; D005260:Female; D053804:Granzymes; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007422:Intestines / Q000276:immunology*; D008297:Male; D008562:Membrane Glycoproteins / Q000032:analysis* / Q000235:genetics; D008875:Middle Aged; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger / Q000032:analysis; D012007:Rectum / Q000276:immunology; D012697:Serine Endopeptidases / Q000032:analysis*
chemical_list: D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D012333:RNA, Messenger; D054353:Perforin; D007371:Interferon-gamma; D053804:Granzymes; D012697:Serine Endopeptidases; C509212:GZMA protein, human