Impairment of CCR6+ and CXCR3+ Th Cell Migration in HIV-1 Infection Is Rescued by Modulating Actin Polymerization

• Published in: The Journal of immunology (1950) 2017-01, Vol.198 (1), p.184-195
• Main Authors: Cecchinato, Valentina, Bernasconi, Enos, Speck, Roberto F, Proietti, Michele, Sauermann, Ulrike, D'Agostino, Gianluca, Danelon, Gabriela, Rezzonico Jost, Tanja, Grassi, Fabio, Raeli, Lorenzo, Schöni-Affolter, Franziska, Stahl-Hennig, Christiane, Uguccioni, Mariagrazia
• Format: Article
• Language: English
• Subjects: Actin; Actins - metabolism; Activation; Animal models; Animals; Antiretroviral agents; Antiretroviral drugs; Antiretroviral therapy; Blood; CCR6 protein; CD14 antigen; CD4 antigen; Cell activation; Cell adhesion & migration; Cell Separation; Chemokines; Chemotaxis, Leukocyte - immunology; Cofilin; CXCR3 protein; Cytoskeleton; Cytoskeleton - metabolism; Drug therapy; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Helper cells; HIV Infections - immunology; HIV-1; Humans; Immune Regulation; Immunohistochemistry; Impairment; Infections; Leukocyte migration; Lymphocytes; Lymphocytes T; Macaca mulatta; Mice; Mice, Inbred C57BL; Migration; Mucosa; Okadaic acid; Organs; Polymerization; Real-Time Polymerase Chain Reaction; Receptors, CCR6 - immunology; Receptors, CXCR3 - immunology; Repopulation; Simian Acquired Immunodeficiency Syndrome - immunology; T cell receptors; T-Lymphocytes, Helper-Inducer - immunology; Trafficking
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1600568

CD4 T cell repopulation of the gut is rarely achieved in HIV-1-infected individuals who are receiving clinically effective antiretroviral therapy. Alterations in the integrity of the mucosal barrier have been indicated as a cause for chronic immune activation and disease progression. In this study, we present evidence that persistent immune activation causes impairment of lymphocytes to respond to chemotactic stimuli, thus preventing their trafficking from the blood stream to peripheral organs. CCR6 and CXCR3 Th cells accumulate in the blood of aviremic HIV-1-infected patients on long-term antiretroviral therapy, and their frequency in the circulation positively correlates to levels of soluble CD14 in plasma, a marker of chronic immune activation. Th cells show an impaired response to chemotactic stimuli both in humans and in the pathogenic model of SIV infection, and this defect is due to hyperactivation of cofilin and inefficient actin polymerization. Taking advantage of a murine model of chronic immune activation, we demonstrate that cytoskeleton remodeling, induced by okadaic acid, restores lymphocyte migration in response to chemokines, both in vitro and in vivo. This study calls for novel pharmacological approaches in those pathological conditions characterized by persistent immune activation and loss of trafficking of T cell subsets to niches that sustain their maturation and activities.