title: Epithelial adhesion molecules can inhibit HIV-1-specific CD8⁺ T-cell functions.
abstract: Under persistent antigenic stimulation, virus-specific CD8⁺ T cells become increasingly dysfunctional and up-regulate several inhibitory molecules such as killer lectin-like receptor G1 (KLRG1). Here, we demonstrate that HIV-1 antigen-specific T cells from subjects with chronic-progressive HIV-1 infection have significantly elevated KLRG1 expression (P < .001); show abnormal distribution of E-cadherin, the natural ligand of KLRG1, in the intestinal mucosa; and have elevated levels of systemic soluble E-cadherin (sE-cadherin) that significantly correlate with HIV-1 viral load (R = 0.7, P = .004). We furthermore demonstrate that in the presence of sE-cadherin, KLRG1(hi) HIV-1-specific CD8⁺ T cells are impaired in their ability to respond by cytokine secretion on antigenic stimulation (P = .002) and to inhibit viral replication (P = .03) in vitro. Thus, these data suggest a critical mechanism by which the disruption of the intestinal epithelium associated with HIV-1 leads to increased systemic levels of sE-cadherin, which inhibits the effector functions of KLRG1(hi)-expressing HIV-1-specific CD8⁺ T cells systemically.
authors.affiliation: Ragon Institute of MGH, MIT, and Harvard, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. hstreeck@partners.org
authors.forename: Hendrik
authors.initials: H
authors.lastname: Streeck
authors.forename: Douglas S
authors.initials: DS
authors.lastname: Kwon
authors.forename: Augustine
authors.initials: A
authors.lastname: Pyo
authors.forename: Michael
authors.initials: M
authors.lastname: Flanders
authors.forename: Mathieu F
authors.initials: MF
authors.lastname: Chevalier
authors.forename: Kenneth
authors.initials: K
authors.lastname: Law
authors.forename: Boris
authors.initials: B
authors.lastname: Jülg
authors.forename: Kasper
authors.initials: K
authors.lastname: Trocha
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Jolin
authors.forename: Melis N
authors.initials: MN
authors.lastname: Anahtar
authors.forename: Jeff
authors.initials: J
authors.lastname: Lian
authors.forename: Ildiko
authors.initials: I
authors.lastname: Toth
authors.forename: Zabrina
authors.initials: Z
authors.lastname: Brumme
authors.forename: J Judy
authors.initials: JJ
authors.lastname: Chang
authors.forename: Tyler
authors.initials: T
authors.lastname: Caron
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Rodig
authors.forename: Danny A
authors.initials: DA
authors.lastname: Milner
authors.forename: Alicja
authors.initials: A
authors.lastname: Piechoka-Trocha
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Kaufmann
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: Marcus
authors.initials: M
authors.lastname: Altfeld
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015820:Cadherins / Q000276:immunology / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000276:immunology / Q000378:metabolism; D002469:Cell Separation; D003106:Colon / Q000276:immunology / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015658:HIV Infections / Q000276:immunology* / Q000378:metabolism; D015497:HIV-1 / Q000276:immunology; D006801:Humans; D007150:Immunohistochemistry; D037181:Lectins, C-Type / Q000096:biosynthesis* / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D011971:Receptors, Immunologic; D015534:Trans-Activators / Q000096:biosynthesis* / Q000276:immunology; D014779:Virus Replication / Q000276:immunology
chemical_list: D015820:Cadherins; D015815:Cell Adhesion Molecules; C113413:KLRG1 protein, human; D037181:Lectins, C-Type; D011971:Receptors, Immunologic; D015534:Trans-Activators