Epithelial adhesion molecules can inhibit HIV-1–specific CD8+ T-cell functions

• Published in: Blood Vol. 117; no. 19; pp. 5112 - 5122
• Main Authors: Streeck, Hendrik, Kwon, Douglas S., Pyo, Augustine, Flanders, Michael, Chevalier, Mathieu F., Law, Kenneth, Jülg, Boris, Trocha, Kasper, Jolin, Jonathan S., Anahtar, Melis N., Lian, Jeff, Toth, Ildiko, Brumme, Zabrina, Chang, J. Judy, Caron, Tyler, Rodig, Scott J., Milner, Danny A., Piechoka-Trocha, Alicja, Kaufmann, Daniel E., Walker, Bruce D., Altfeld, Marcus
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 12.05.2011; Americain Society of Hematology; American Society of Hematology
• Subjects: Biological and medical sciences; Cadherins - immunology; Cadherins - metabolism; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cell Adhesion Molecules - immunology; Cell Adhesion Molecules - metabolism; Cell Separation; Colon - immunology; Colon - metabolism; Enzyme-Linked Immunosorbent Assay; Female; Flow Cytometry; Fluorescent Antibody Technique; Hematologic and hematopoietic diseases; HIV Infections - immunology; HIV Infections - metabolism; HIV-1 - immunology; Human viral diseases; Humans; Immunobiology; Immunohistochemistry; Immunology; Infectious diseases; Lectins, C-Type - biosynthesis; Lectins, C-Type - immunology; Life Sciences; Lymphocyte Activation - immunology; Male; Medical sciences; Receptors, Immunologic; Trans-Activators - biosynthesis; Trans-Activators - immunology; Vascular Biology; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Virus Replication - immunology; Immunopathology; Hematology; HIV-1 virus; Cell adhesion molecule; Retroviridae; AIDS; Immune deficiency; Lentivirus; Infection; Virus; Viral disease; Inhibitor; Human immunodeficiency virus; CD8 T lymphocyte
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2010-12-321588

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, KLRG1hi 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 KLRG1hi-expressing HIV-1–specific CD8+ T cells systemically.