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Mediators of Inflammation
Volume 2016 (2016), Article ID 1759027, 15 pages
http://dx.doi.org/10.1155/2016/1759027
Research Article

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

1Unidad de Inmunovirología, Servicio de Biología Molecular en Medicina, Hospital Civil de Guadalajara “Fray Antonio Alcalde”, 44280 Guadalajara, JAL, Mexico
2Departamento de Biología Molecular, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, 44100 Guadalajara, JAL, Mexico
3Departamento de Fisiología, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, 44100 Guadalajara, JAL, Mexico
4Departamento de Medicina Veterinaria, Centro Universitario de Ciencias Biológicas y Agropecuarias, Universidad de Guadalajara, 44100 Guadalajara, JAL, Mexico
5Servicio de Biología Molecular en Medicina, Hospital Civil of Guadalajara “Fray Antonio Alcalde”, 44280 Guadalajara, JAL, Mexico
6Departamento de Clínicas Médicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, 44100 Guadalajara, JAL, Mexico
7Instituto Tecnológico de Tlajomulco, 45640 Tlajomulco, JAL, Mexico
8Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, 62210 Ciudad de México, Mexico

Received 31 March 2016; Revised 7 June 2016; Accepted 26 June 2016

Academic Editor: José César Rosa Neto

Copyright © 2016 Karla F. Corral-Jara et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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.