title: Conjugated Bilirubin Differentially Regulates CD4+ T Effector Cells and T Regulatory Cell Function through Outside-In and Inside-Out Mechanisms: The Effects of HAV Cell Surface Receptor and Intracellular Signaling.
abstract: We recently reported an immune-modulatory role of conjugated bilirubin (CB) in hepatitis A virus (HAV) infection. During this infection the immune response relies on CD4+ T lymphocytes (TLs) and it may be affected by the interaction of HAV with its cellular receptor (HAVCR1/TIM-1) on T cell surface. How CB might affect T cell function during HAV infection remains to be elucidated. Herein, in vitro stimulation of CD4+ TLs from healthy donors with CB resulted in a decrease in the degree of intracellular tyrosine phosphorylation and an increase in the activity of T regulatory cells (Tregs) expressing HAVCR1/TIM-1. A comparison between CD4+ TLs from healthy donors and HAV-infected patients revealed changes in the TCR signaling pathway relative to changes in CB levels. The proportion of CD4+CD25+ TLs increased in patients with low CB serum levels and an increase in the percentage of Tregs expressing HAVCR1/TIM-1 was found in HAV-infected patients relative to controls. A low frequency of 157insMTTTVP insertion in the viral receptor gene HAVCR1/TIM-1 was found in patients and controls. Our data revealed that, during HAV infection, CB differentially regulates CD4+ TLs and Tregs functions by modulating intracellular pathways and by inducing changes in the proportion of Tregs expressing HAVCR1/TIM-1.
authors: Unidad de Inmunovirología, Servicio de Biología Molecular en Medicina, Hospital Civil de Guadalajara "Fray Antonio Alcalde", 44280 Guadalajara, JAL, Mexico; Departamento de Biología Molecular, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, 44100 Guadalajara, JAL, Mexico.
authors: Karla F
authors: KF
authors: Corral-Jara
authors: Unidad de Inmunovirología, Servicio de Biología Molecular en Medicina, Hospital Civil de Guadalajara "Fray Antonio Alcalde", 44280 Guadalajara, JAL, Mexico; Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, 44100 Guadalajara, JAL, Mexico.
authors: Jorge L
authors: 0000-0002-4198-6211
authors: JL
authors: Trujillo-Ochoa
authors: Departamento de Medicina Veterinaria, Centro Universitario de Ciencias Biológicas y Agropecuarias, Universidad de Guadalajara, 44100 Guadalajara, JAL, Mexico.
authors: Mauricio
authors: 0000-0001-9271-3865
authors: M
authors: Realpe
authors: Servicio de Biología Molecular en Medicina, Hospital Civil of Guadalajara "Fray Antonio Alcalde", 44280 Guadalajara, JAL, Mexico; Departamento de Clínicas Médicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, 44100 Guadalajara, JAL, Mexico.
authors: Arturo
authors: 0000-0003-4784-748X
authors: A
authors: Panduro
authors: Instituto Tecnológico de Tlajomulco, 45640 Tlajomulco, JAL, Mexico.
authors: Juan F
authors: JF
authors: Gómez-Leyva
authors: Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, 62210 Ciudad de México, Mexico.
authors: Yvonne
authors: Y
authors: Rosenstein
authors: Departamento de Biología Molecular, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, 44100 Guadalajara, JAL, Mexico; Servicio de Biología Molecular en Medicina, Hospital Civil of Guadalajara "Fray Antonio Alcalde", 44280 Guadalajara, JAL, Mexico.
authors: Alexis
authors: A
authors: Jose-Abrego
authors: Departamento de Biología Molecular, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, 44100 Guadalajara, JAL, Mexico; Servicio de Biología Molecular en Medicina, Hospital Civil of Guadalajara "Fray Antonio Alcalde", 44280 Guadalajara, JAL, Mexico.
authors: Sonia
authors: S
authors: Roman
authors: Unidad de Inmunovirología, Servicio de Biología Molecular en Medicina, Hospital Civil de Guadalajara "Fray Antonio Alcalde", 44280 Guadalajara, JAL, Mexico; Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, 44100 Guadalajara, JAL, Mexico.
authors: Nora A
authors: 0000-0002-9719-4838
authors: NA
authors: Fierro
mesh_terms: D000293:Adolescent; D000328:Adult; D001663:Bilirubin / Q000494:pharmacology*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D002478:Cells, Cultured; D005260:Female; D000072596:Hepatitis A Virus Cellular Receptor 1 / Q000235:genetics; D030041:Hepatitis A virus / Q000378:metabolism*; D006801:Humans; D020381:Interleukin-17 / Q000378:metabolism; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D015398:Signal Transduction / Q000187:drug effects; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects* / Q000378:metabolism*; D055815:Young Adult
chemical_list: C491143:HAVCR1 protein, human; D000072596:Hepatitis A Virus Cellular Receptor 1; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D001663:Bilirubin